EP1806344A1 - Optically active 4,4-disubstituted oxazolidine derivative and method for producing same - Google Patents

Optically active 4,4-disubstituted oxazolidine derivative and method for producing same Download PDF

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EP1806344A1
EP1806344A1 EP05799393A EP05799393A EP1806344A1 EP 1806344 A1 EP1806344 A1 EP 1806344A1 EP 05799393 A EP05799393 A EP 05799393A EP 05799393 A EP05799393 A EP 05799393A EP 1806344 A1 EP1806344 A1 EP 1806344A1
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group
methyl
general formula
compound
substituted
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French (fr)
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EP1806344A4 (en
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Toshihiko c/o Sankyo Company Limited ONODA
Yoshitaka c/o Sankyo Company Limited NAKAMURA
Makoto c/o Sankyo Company Limited YAMAOKA
Tadahiro c/o Sankyo Company Limited TAKEDA
Noritada c/o Sankyo Company Limited SATO
Masayoshi c/o Sankyo Company Limited JIN
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Sankyo Co Ltd
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Sankyo Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/04—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D263/06—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by oxygen atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/04—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the present invention relates to optically active 4,4-di-substituted oxazolidine derivatives and procedures for their preparation.
  • the optically active 4,4-di-substituted oxazolidine derivatives of the present invention have advantage as useful synthetic intermediates in new stereoselective industrial manufacturing methods of optically active ⁇ , ⁇ -di-substituted ⁇ -amino acid derivatives and optically active ⁇ , ⁇ -di-substituted ⁇ -amino alcohol derivatives.
  • optically active ⁇ , ⁇ -di-substituted ⁇ -amino acid derivatives through optically active 4,4-di-substituted oxazolidine derivatives as a synthetic intermediate
  • methods described by Dieter Seebach, et al. (refer to non-patent literature 1 and non-patent literature 2) and by Carlos Cativiela, et al. (refer to non-patent literature 3 and non-patent literature 4) have been known.
  • the method described by Carlos Cativiela, et al. is a method that includes the processes of diastereoselective alkylation using an optically active cyano ester compound and Sharpless asymmetric oxidation, but in the former process, the low yield, low stereoselectivity and numerous reaction steps are a disadvantage, and in the latter process, the use of a peroxidized compound and numerous reaction steps are a disadvantage, and these procedures are also unsuitable for industrial large-scale synthesis.
  • optically active 4,4-di-substituted oxazolidine derivatives have been used as a synthetic intermediate for the preparation of glutamate receptor antagonists, which are optically active ⁇ , ⁇ -di-substituted ⁇ -amino acid derivatives, and its usefulness have already been known.
  • Glutamate receptor antagonists have been reported as effective against epilepsy, brain defects following heart pypass surgery and/or transplantation, attack, cerebral ischemia, pain, spinal cord injury, head trauma, hypoxia at birth, cardiac arrest and hypoglycemia-induced damage, anxiety, neurodegenerative diseases, Huntington's chorea, AIDS-induced dementia, eye damage, retinopathy, cognitive deficiency, Parkinson's disease, Alzheimer's disease, multiple sclerosis, or the like (refer to non-patent literature 5 to 7 and patent literature 1).
  • optically active ⁇ , ⁇ -di-substituted ⁇ -amino alcohol derivatives exert an immunosuppressive activity based on a novel mechanism of action (refer to non-patent literatures 8 to 10 and patent literature 2), and the optically active 4,4-di-substituted oxazolidine derivatives of the present invention are considered to be useful synthetic intermediates for the preparation of the optically active ⁇ , ⁇ -di-substituted ⁇ -amino alcohol derivatives.
  • the subject of the present invention is to provide less-expensive and more efficient stereoselective procedures for the preparation of optically active ⁇ , ⁇ -di-substituted ⁇ -amino acid derivatives and optically active ⁇ , ⁇ -di-substituted ⁇ -amino alcohol derivatives.
  • glutamate receptor antagonists that are useful for therapy against epilepsy, brain deficit following epilepsy, heart bypass surgery, and transplantation of an organ, attack, ischemic brain, pain, spinal cord injury, head trauma, hypoxia at birth, cardiac failure and hypoglycemic damage, anxiety, neurodegenerative diseases, Huntington's disease, AIDS-induced dementia, eye damage, retinopathy, cognitive disorder, Parkinson's disease, Alzheimer's disease, or multiple sclerosis, or the like; or immunosuppressive agents that are useful for therapy against suppression of rejection symptoms caused by organ transplantation or skin transplantation, or for therapy against autoimmune diseases such as rheumatic arthritis, psoriasis, multiple sclerosis, inflammatory bowel disease, lupus erythematosus nephritis, glomerular nephritis, insulin resistant diabetes mellitus, atopic dermatitis, and the like.
  • autoimmune diseases such as rheumatic arthritis, psoriasis, multiple sclerosis,
  • the inventors of the present invention have diligently investigated for many years into various procedures for the preparation of ⁇ , ⁇ -di-substituted ⁇ -amino acid derivatives and optically active ⁇ , ⁇ -di-substituted ⁇ -amino alcohol derivatives in order to solve the subject described above, and discovered a synthetic procedure comprising processes through optically active 4,4-di-substituted oxazolidine derivatives shown below and furthermore a preparation procedure by which the substituted-methylenephosphonium salt which is useful as the intermediate can be obtained conveniently in high yield, and consequently, the inventors completed the present invention.
  • the present invention provides
  • the "C 1 -C 3 alkyl group" in the definition of R 1 can be, for example, a methyl, ethyl, 2-methylethyl or n-propyl group, and is preferably an ethyl group.
  • the "C 2 -C 3 alkenyl group" in the definition of R 1 can be, for example, a vinyl, 2-methylvinyl or n-propenyl group, and is preferably a vinyl group.
  • the "C 1 -C 6 alkyl group" in the definitions of R, R 2 and R 4 can be, for example, a methyl, ethyl, n-propyl, i-propyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, diethylmethyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl or 2-ethylbutyl group, and is preferably a C 1 -C 4 alkyl group, and
  • the "C 2 -C 6 alkenyl group" in the definitions of R and R 4 can be, for example, a vinyl, allyl, 1-methyl-2-propenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl, 2-ethyl-2-propenyl, 1-butenyl, 2-butenyl, 1-methyl-2-butenyl, 1-methyl-1-butenyl, 3-methyl-2-butenyl, 1-ethyl-2-butenyl, 3-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 1-ethyl-3-butenyl, 1-pentenyl, 2-pentenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-pentenyl, 1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 4-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 2-methyl-4-
  • the "C 3 -C 10 cycloalkyl group" in the definition of R 2 can be, for example, a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl or adamantyl group, and is preferably a C 5 -C 10 cycloalkyl group and more preferably a cyclohexyl group or an adamantyl group.
  • the "C 2 -C 6 alkanoyl group" in the definition of R 3 can be, for example, an acetyl, propionyl, isopropionyl, n-butanoyl, isobutanoyl, n-pentanoyl, isopentanoyl, 2-methylbutanoyl, pivaloyl, n-hexanoyl, 2-methylpentanoyl, 3-methylpentanoyl or hexanoyl group, and is preferably a C 2 -C 4 alkanoyl group and more preferably an acetyl group.
  • the "C 1 -C 6 alkyloxycarbonyl group" in the definition of R 3 can be, for example, a methoxycarbonyl, ethoxycarbonyl, propyloxycarbonyl, n-butoxycarbonyl, t-butoxycarbonyl, pentyloxycarbonyl or hexyloxycarbonyl group, and is preferably a C 1 -C 4 alkyloxycarbonyl group and more preferably a methoxycarbonyl group.
  • halogen atom in the definitions of Substituent groups A and Y can be, for example, a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
  • the "C 1 -C 8 alkyl group" in the definitions of Substituent groups A and Y can be, for example, a group shown as the "C 1 -C 6 alkyl group” in the definitions described above, a heptyl group or an octyl group, and is preferably a C 6 -C 8 alkyl group and more preferably an octyl group.
  • the "C 1 -C 8 alkoxyl group" in the definitions of Substituent groups A and Y can be, for example, a methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, s-butoxy, t-butoxy, n-pentyloxy, isopentyloxy, 2-methylbutoxy, neopentyloxy, 1-ethylpropoxy, n-hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyloxy, 1-methylpentyloxy, 3,3-dimethylbutoxy, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutoxy, 2,3-dimethylbutoxy, 2-ethylbutoxy, heptyloxy or octyloxy group, and preferably a C
  • the "C 2 -C 8 alkanoyl group" in the definitions of Substituent groups A and Y can be, for example, a group shown as the "C 2 -C 6 alkanoyl group” in the definitions described above, a heptanoyl group or an octanoyl group, and is preferably a C 6 -C 8 alkanoyl group and more preferably an octanoyl group.
  • the "phosphonium salt" in the definition of W can be, for example, trimethylphosphonium chloride, trimethylphosphonium bromide, trimethylphosphonium iodide, triethylphosphonium chloride, triethylphosphonium bromide, triethylphosphonium iodide, tripropylphosphonium chloride, tripropylphosphonium bromide, tripropylphosphonium iodide, tributylphosphonium chloride, tributylphosphonium bromide, tributylphosphonium iodide, triphenylphosphonium chloride, triphenylphosphonium bromide or triphenylphosphonium iodide, and is preferably triphenylphosphonium chloride.
  • the "phosphonic acid ester" in the definition of W can be, for example, dimethyl phosphonate, diethyl phosphonate, ditrifluoroethyl phosphonate, diphenyl phosphonate, or di-o-tolyl phosphonate, and is preferably diethyl phosphonate:
  • the "C 1 -C 6 alkyl group" in the definition of X can be, for example, a methyl, ethyl, n-propyl, i-propyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, diethylmethyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl or 2-ethylbutyl group, and is preferably a C 1 -C 4 alkyl group, and more preferably a
  • the "silyl group" in the definition of X can be, for example, a trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, t-butyldimethylsilyl, methyldiisopropylsilyl, methyldi-t-butylsilyl, triisopropylsilyl, methyldiphenylsilyl, isopropyldiphenylsilyl, butyldiphenylsilyl or phenyldiisopropylsilyl group, and is preferably a trimethylsilyl, triethylsilyl, isopropyldimethylsilyl or t-butyldimethylsilyl group.
  • the "acyl group" in the definition of X can be, for example, a formyl, carboxyl, carbamoyl, C 1 -C 6 alkylcarbonyl (for example, an acetyl, butanoyl, isobutanoyl or isopentanoyl group), C 1 -C 6 alkoxycarbonyl (for example, a methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl or t-butoxycarbonyl group), C 6 -C 14 arylcarbonyl (for example, a benzoyl, 1-naphthoyl or 2-naphthoyl group), C 6 -C 14 aryloxycarbonyl (for example, a phenyloxycarbonyl or naphthyloxycarbonyl group), C 7 -C 13 aralkyloxycarbonyl (for example, a benzyloxycarbonyl or phenethyl)
  • X is preferably a vinylene group, a sulfur atom or a nitrogen atom substituted with a C 1 -C 6 alkyl group and more preferably a vinylene group, a sulfur atom or a nitrogen atom substituted with a methyl group.
  • Y is preferably a hydrogen atom, a halogen atom, a C 1 -C 8 alkyl group, a C 1 -C 8 alkoxyl group or a C 2 -C 8 alkanoyl group and more preferably a hydrogen atom, a halogen atom, a methyl group, an octyl group, a methoxyl group or a heptyloxy group.
  • the "C 1 -C 6 alkyl group" of the "C 1 -C 6 alkyl group which may optionally be substituted with substituent(s) selected from Substituent group ⁇ " in the definitions of R 5 can be, for example, a methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl or 2-ethylbutyl group, and is preferably a methyl, ethyl, propyl, isopropyl, butyl or isobutyl group, and more preferably a methyl or ethyl group.
  • the "which may optionally be substituted with substituent(s) selected from Substituent group ⁇ " of the "C 1 -C 6 alkyl group which may optionally be substituted with substituent(s) selected from Substituent group ⁇ " described above means that substitutable positions of said C 1 -C 6 alkyl group may optionally be substituted with from 1 to 3 substituents selected from Substituent group ⁇ .
  • the "5- to 10-membered aromatic ring" of the "5- to 10-membered aromatic group which may optionally be substituted with substituent(s) selected from Substituent group ⁇ " in the definition of R 5 shown above is, for example, a 5- to 10-membered aromatic hydrocarbon ring or a 5- to 10-membered aromatic heterocyclic ring.
  • a 5- to 10-membered aromatic hydrocarbon ring is preferably a benzene ring or a naphthalene ring, and more preferably a benzene ring.
  • a 5- to 10-membered aromatic heterocyclic ring is preferably a 5- to 10-membered aromatic heterocyclic ring which contains 1 to 4 heteroatoms selected from the group consisting of an oxygen, sulfur and nitrogen atom in addition to the carbon atoms as the ring-composing atoms, and is, for example, furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, imidazole, pyrazole, 1,2,3-oxadiazole, furazan, 1,2,3-thiadiazole, 1,2,3-triazole, pyridine, pyridazine, pyrimidine, triazine, benzofuran, isobenzofuran, benzo[b]thiophene, indole, isoindole, 1H-indazole, benzimidazole, benzoxazole, 1,2-benzisoxazole, bonzothiazole, 1,2-
  • the "4- to 8-membered nitrogen-containing heterocyclic group" of the " 4- to 8-membered nitrogen-containing heterocyclic group which may optionally be substituted with substituent(s) selected from Substituent group ⁇ " is, for example, azetidine, pyrrolidine, piperidine, azepan, morpholine or piperazine, and preferably pyrrolidine or piperidine.
  • halogen atom is, for example, a fluorine, chlorine, bromine or iodine atom.
  • C 1 -C 8 alkyl group is, for example, a methyl, ethyl, n-propyl, i-propyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, heptyl or octyl group.
  • the "C 1 -C 8 alkoxyl group” is a group wherein a terminal of the "C 1 -C 8 alkyl group” shown above is bound to an oxygen atom.
  • the "C 1 -C 8 alkylthio group” is a group wherein a terminal of the "C 1 -C 8 alkyl group” shown above is bound to a sulfur atom.
  • the "acyl group” can be, for example, a group of formula -COR 3' , -CO 2 R 3' , -SO 2 R 3' , -SOR 3' , -PO 3 R 3' R 4' , -CO-NR 3a R 4a or-CS-NR 3a R 4a [wherein, R 3' and R 4' are the same or different and each represents a hydrogen atom, a hydrocarbon group or a heterocyclic group and R 3a and R 4a groups are the same or different and each represents a hydrogen atom, a hydrocarbon group or a heterocyclic group, or R 3a and R 4a groups together with an adjacent nitrogen atom may form a nitrogen-containing heterocyclic ring].
  • the "hydrocarbon group” described for R 3' , R 4' , R 3a or R 4a is a "C 1 -C 6 alkyl group", a "C 3 -C 6 cycloalkyl group", a "C 6 -C 10 aryl group” or a "C 7 -C 13 aralkyl group”.
  • the "nitrogen-containing heterocyclic ring" formed by R 3a and R 4a groups together with an adjacent nitrogen atom is a 5- to 7-membered nitrogen-containing heterocyclic ring which may contain at least one nitrogen atom and 1 or 2 heteroatoms selected from the group consisting of an oxygen, sulfur and nitrogen atom in addition to the carbon atoms as the ring-composing atoms, and is preferably pyrrolidine, imidazolidine, pyrazolidine, piperidine, piperazine, morpholine or thiomorpholine.
  • acyl group can be, for example, a formyl, carboxyl, carbamoyl, C 1 -C 6 alkylcarbonyl (for example, an acetyl, butanoyl, isobutanoyl or isopentanoyl group), C 1 -C 6 alkoxycarbonyl (for example, a methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl or t-butoxycarbonyl group), C 6 -C 14 arylcarbonyl (for example, a benzoyl, 1-naphthoyl or 2-naphthoyl group), C 6 -C 14 aryloxycarbonyl (for example, a phenyloxycarbonyl or naphthyloxycarbonyl group), C 7 -C 13 aralkyloxycarbonyl (for example, a benzyloxycarbonyl or phenethyloxycarbonyl group), mono- or di-C
  • the "C 1 -C 6 alkyl group" of the "C 1 -C 6 alkyl group which may optionally be substituted with substituent(s) selected from Substituent group ⁇ " and the "5- to 10-membered aromatic group” of the "5- to 10-membered aromatic group which may optionally be substituted with substituent(s) selected from Substituent group ⁇ " in the definition of R 6 described above have the same meanings as those indicated in the definition of R 5 described above.
  • the "C 1 -C 6 alkoxyl group which may optionally be substituted with substituent(s) selected from Substituent group ⁇ " in the definition of R 6 described above is a group wherein a terminal of the "C 1 -C 6 alkyl group which may optionally be substituted with substituent(s) selected from Substituent group ⁇ " in the definition of R 5 described above is bound to an oxygen atom.
  • the "5- to 10-membered aromatic-oxy group which may optionally be substituted with substituent(s) selected from Substituent group ⁇ " in the definition of R 6 described above is a group wherein a terminal of the "5- to 10-membered aromatic group which may optionally be substituted with substituent(s) selected from Substituent group ⁇ " in the definition of R 5 described above is bound to an oxygen atom.
  • acyl group in the definition of R 7 described above has the same meaning as the "acyl group” indicated in the definition of Substituent group ⁇ , and is preferably a C 1 -C 6 alkylcarbonyl group (for example, an acetyl, butanoyl or isobutanoyl group).
  • C 1 -C 6 alkyl group which may optionally be substituted with from 1 to 3 halogen atoms can be, for example, a fluoromethyl, difluoromethyl, trifluoromethyl, difluoroethyl or trifluoroethyl group, and preferably a trifluoromethyl group.
  • phenyl group which may optionally be substituted with from 1 to 3 substituents selected from the group consisting of a halogen atom and a methyl group in the definition of R c described above can be, for example, a 4-fluorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 4-methylphenyl or 3,4-dimethylphenyl group, and is preferably a 4-dimethylphenyl group.
  • R 5 described above is preferably a C 1 -C 10 alkyl group which may optionally be substituted with substituent(s) selected from Substituent group ⁇ or a 4- to 8-membered nitrogen-containing heterocyclic group formed by two R 5 groups together with a nitrogen atom to which they are bound which may optionally be substituted with substituent(s) selected from Substituent group ⁇ , more preferably a C 1 -C 6 alkyl group, or pyrrolidine or piperidine formed by two R 1 groups together with a nitrogen atom to which two R 5 groups are bound, and still more preferably a methyl or ethyl group, or pyrrolidine or piperidine formed by two R 5 groups together with a nitrogen atom to which they are bound.
  • R 6 described above is preferably a C 1 -C 6 alkyl group or a 5- to 10-membered aromatic ring group, and more preferably a phenyl group.
  • R 7 described above is preferably a C 1 -C 6 alkylcarbonyl group, and more preferably an acetyl group.
  • V described above is preferably a chlorine atom, a bromine atom or an iodine atom, and more preferably a chlorine or iodine atom.
  • X described above is preferably a vinylene group, a sulfur atom or a nitrogen atom substituted with a C 1 -C 6 alkyl group, and more preferably a vinylene group, a sulfur atom or a nitrogen atom substituted with a methyl group.
  • Y described above is preferably a hydrogen atom, a halogen atom, a C 1 -C 8 alkyl group, a C 1 -C 8 alkoxyl group or C 2 -C 8 alkanoyl group, and more preferably a hydrogen atom, a halogen atom, a methyl group, an octyl group, a methoxyl group or a heptyloxy group.
  • Substituent group ⁇ described above is preferably a halogen atom, a C 1 -C 8 alkyl group, a C 1 -C 8 alkoxyl group or an acyl group, more preferably a C 1 -C 6 alkyl group or a C 1 -C 6 alkoxyl group, and particularly preferably a methyl group or a methoxyl group.
  • Such a salt is, for example, an inorganic base salt, an organic base salt, an inorganic acid salt, an organic acid salt, or a basic or acidic amino acid salt.
  • the inorganic base salt is preferably an alkali metal salt such as a sodium salt, potassium salt or the like; an alkaline earth metal salt such as a calcium salt, magnesium salt or the like; an aluminum salt; an ammonium salt or the like.
  • the organic base salt is preferably a trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, diethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N-dibenzylethylenediamine salt or the like.
  • the inorganic acid salt is preferably a hydrochloride, a hydrobromide, a nitrate, a sulfate, a phosphate or the like.
  • the organic acid salt is preferably a formate, an acetate, a trifluoroacetate, a fumarate, an oxalate, a tartrate, a maleate, a citrate, a succinate, a malate, methanesulfonate, benzenesufonate, p-toluenesulfonate or the like.
  • the compounds having the general formulae (I), (Ia), (Ib), (Ic) and (Id) of the present invention have an asymmetric carbon atom in their structures, and can exist as optical isomers due to such asymmetric carbon atom.
  • a single optical isomer and mixtures of optical isomers are represented as a single chemical formula (I), (Ia), (Ib), (Ic) or (Id), individually.
  • the present invention encompasses both individual optical isomers and mixtures thereof in any ratio.
  • preferred compounds are the compounds of Exemplification Compound Nos. 1-2, 7-8, 13-14, 19-20, 25-26, 31-32, 37-38, 43-44, 49-50, 55-56, 61-62, 67-68, 73-74, 79-80, 85-86, 91-92, 97-98, 103-104, 109-110, 115-116, 121-122, 127-128, 133-134, 139-140, 145-146, 151-152, 157-158, 163-164, 169-170, 175-176, 181-182, 187-188, 193-194, 199-200, 205-206.
  • More preferred compounds are the compounds of Exemplification Compound Nos.1,7,13,19,25,31,37,43,49,55,61,67,73,79,85,91,97,103,109, 115,121,127,133,139,145,151,157,163,169,175,181,187,193,199,205.
  • preferred compounds are the compounds of Exemplification Compound Nos. 1, 4, 7,10, 13, 16, 19,22,25,28,31,34,37,40, 43, 46, 49, 52, 55, 58, 61, 64, 67, 70, 73, 76, 79, 82, 85, 88, 91, 94, 97, 100, and 103.
  • More preferred compounds are the compounds of Exemplification Compound Nos. 1, 4, 7, 10, 13, 16, 19, 22, 25, 28, 31, 34, 37, 40, 43, 46, 49, 52, 55, 58, and 61.
  • More preferred compounds are the compounds of Exemplification Compound Nos.:
  • the present invention is useful for providing the optically active 4,4-di-substituted oxazolidine derivatives and procedures for their preparation.
  • the preparation procedures of the present invention have excellent advantages in the following respects, compared with the prior art: 1) increase in yield, 2) improvement in stereoselectivity, 3) extremely low-temperature reaction which is unsuitable for industrial large-scale synthesis is not necessary, and 4) column-chromatographic purification of intermediates is not needed in any step of these synthetic processes.
  • the compounds having the general formula (Id), which are the optically active 4,4-di-substituted oxazolidine derivatives encompassed in the present invention are useful as synthetic intermediates in the preparation of optically active ⁇ , ⁇ -di-substituted ⁇ -amino acid derivatives having an excellent glutamate receptor antagonistic action or optically active ⁇ , ⁇ -di-substituted ⁇ -amino alcohol derivatives having new immunosuppressive action.
  • an immunosuppressive agent having a new mode action can be synthesized from the compounds of the general formula (Id) of the present invention [wherein, R 2 and R 3 have the same meanings as those indicated hereinbefore, R 4 represents a methyl group, X represent a vinylene group, and Y represents a heptyloxy group] by removing R 2 and R 3 groups, both of which are protecting groups, by treatment with an acid, a base or the like according to conventional procedures.
  • the substituted methylenephosphonium salt which is useful as a synthetic intermediate in the preparation of the compounds having the general formula (Id) and various kinds of medicines can be obtained conveniently in a high yield.
  • the substituted methylenephosphonium salt having the general formula (IV'-b) or (IV'-c) prepared by the present invention is, for example, as shown in the following reaction scheme, useful as the intermediate in the preparation of immunosuppressive agents having the general formula (VI'-b) or (VI'-c) disclosed in W003/059880 .
  • Y represents an ethylene group, a vinylene group, an ethynylene group, a group of formula -E-CH 2 - (wherein, E represents a carbonyl group, a group of formula -CH(OH)-, an oxygen atom, a sulfur atom or a group of formula - NH-), Z represents a single bond, a C 1 -C 10 alkylene group or a C 1 -C 10 alkylene group which has an oxygen atom or a sulfur atom in or at an end of the carbon chain, and R 5 represents a hydrogen atom, a cycloalkyl group, an aryl group or a heterocyclic group]
  • the substituted methylenephosphonium salt having the general formula (IV'-d) prepared by the present invention is useful since the synthetic intermediate (VI-d) in the preparation of the compound having the general formula (VI'-d) disclosed in WO94/08943 , which is used as an immunosuppressive agent, can be prepared by reacting this invented compound (IV'-d) with a compound having a formula (D) described in Bioorganic and Medicinal Chemistry, 11 (2003) 2529-2539 .
  • R c represents a C 1 -C 10 alkyl group or the like
  • X represents a halogen atom
  • the compounds of the present invention can be prepared according to the procedures described below.
  • the compounds employed in the invented procedures are generally known compounds and can be prepared from known compounds according to known procedures, but some of them are commercially available.
  • known procedures described above there are the procedures described, for example, in “ Organic Functional Group Preparation”, Second Edition, Academic Press, Inc., 1989 , and “ Comprehensive Organic Transformations”, VCH Publishers Inc., 1989 .
  • Such functional group is, for example, a hydroxyl group, a carboxyl group, a hydroxyl group, a carbonyl group and an amino group
  • protecting groups are found in Green and Wuts: "Protective Groups in Organic Synthesis", 3rd edition, John Willey and Sons, Inc., 1999, and a suitable protecting group for them can be used depending on the reaction conditions.
  • the protecting group employed for the carboxyl group is, for example, a C 1 -C 6 alkyl (for example, a methyl, ethyl, propyl, isopropyl, butyl or t-butyl group), C 7 -C 10 aralkyl (for example, a benzyl group), phenyl, trityl, silyl (for example, a trimethylsilyl, triethylsilyl, dimethylphenylsilyl, t-butyldimethylsilyl or t-butyldiethylsilyl group), or C 2 -C 6 alkenyl group (for example, a 1-allyl group).
  • a C 1 -C 6 alkyl for example, a methyl, ethyl, propyl, isopropyl, butyl or t-butyl group
  • C 7 -C 10 aralkyl for example, a benzyl group
  • These groups may optionally be substituted with from 1 to 3 halogen atoms (for example, a fluorine, chlorine, bromine or iodine atom), a C 1 -C 6 alkoxyl group (for example, a methoxy, ethoxy or propoxy group), or a nitro group.
  • halogen atoms for example, a fluorine, chlorine, bromine or iodine atom
  • C 1 -C 6 alkoxyl group for example, a methoxy, ethoxy or propoxy group
  • the protecting group employed for the hydroxyl group is, for example, a C 1 -C 6 alkyl (for example, a methyl, ethyl, propyl, isopropyl, butyl or t-butyl group), phenyl, trityl, C 7 -C 11 aralkyl (for example, a benzyl group), formyl, C 1 -C 6 alkylcarbonyl (for example, an acetyl or propionyl group), benzoyl, C 7 -C 11 aralkylcarbonyl (for example, a benzylcarbonyl group), 2-tetrahydropyranyl, 2-tetrahydrofuranyl, silyl (for example, a trimethylsilyl, triethylsilyl, dimethylphenylsilyl, t-butyldimethylsilyl or t-butyldiethylsilyl group) or C 2 -C 6 alken
  • These groups may optionally be substituted with from 1 to 3 halogen atoms (for example, a fluorine, chlorine, bromine or iodine atom), a C 1 -C 6 alkyl group (for example, a methyl, ethyl or n-propyl group), a C 1 -C 6 alkoxyl group (for example, a methoxy, ethoxy or propoxy group) or a nitro group.
  • halogen atoms for example, a fluorine, chlorine, bromine or iodine atom
  • a C 1 -C 6 alkyl group for example, a methyl, ethyl or n-propyl group
  • a C 1 -C 6 alkoxyl group for example, a methoxy, ethoxy or propoxy group
  • the protecting group employed for the carbonyl group is, for example, a cyclic acetal (for example, 1,3-dioxane) or non-cyclic acetal group (for example, di-C 1 -C 6 alkyl acetal group).
  • the protecting group employed for the amino group is, for example, a formyl, C 1 -C 6 alkylcarbonyl (for example, an acetyl or propionyl group), C 1 -C 6 alkoxycarbonyl (for example, a methoxycarbonyl, ethoxycarbonyl or t-butoxycarbonyl group), benzoyl, C 7 -C 11 aralkylcarbonyl (for example, a benzylcarbonyl group), C 7 -C 14 aralkyloxycarbonyl (for example, a benzyloxycarbonyl or 9-fluorenylmethoxycarbonyl group), trityl, phthaloyl, N,N-dimethylaminomethylene, silyl (for example, a trimethylsilyl, triethylsilyl, dimethylphenylsilyl, t-butyldimethylsilyl or t-butyldiethylsilyl group)
  • These groups may optionally be substituted with from 1 to 3 halogen atoms (for example, a fluorine, chlorine, bromine or iodine atom), a C 1 -C 6 alkoxyl group (for example, a methoxy, ethoxy or propoxy group) or a nitro group.
  • halogen atoms for example, a fluorine, chlorine, bromine or iodine atom
  • C 1 -C 6 alkoxyl group for example, a methoxy, ethoxy or propoxy group
  • the removal of the protecting groups described above is carried out by known procedures such as procedures using an acid, a base, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate or trialkylsilyl halide (for example, trimethylsilyl iodide or trimethylsilyl bromide) or a reduction procedure.
  • the method A is a process for the preparation of a compound having the general formula (Ia).
  • R, R 2 , R 3 and R 4 have the same meanings as those indicated hereinbefore.
  • Step A1 the compound having the general formula (VIII) can be prepared by the esterification of (S)-serine (VII), in Step A2, the compound having the general formula (IX) can be prepared by protecting the amino alcohol compound having the general formula (VIII) obtained above with a R 2 -acetal group, and in Step A3, a compound having the general formula (II) can be prepared by protecting the nitrogen atom of the compound having the general formula (IX) obtained above with R 3 .
  • Step A4 which is a reaction of the present invention, a compound having the general formula (Ia) can be prepared stereoselectively by reacting a compound having the general formula (II) with an alkylating agent in the presence of a coordinating reagent and a base and in the presence of an inert solvent or absence of a solvent.
  • This process is a modified process of the method by Dieter Seebach et al., and is improved to enable this invented procedure to be applied to industrial large-scale manufacturing.
  • the compound having the general formula (Ia) is synthesized by adding a base first to the compound of the general formula (II) in which R is a methyl group, R 2 is a t-butyl group and R 3 is a formyl group (this compound is different from the invented compound in respect that R 3 is a formyl group) and followed by addition of an alkylating agent to the resulting mixture, but the desired compound can be obtained only in the yield of about 40 to 70 %.
  • the compound of the general formula (Ia) can be synthesized in a high yield by addition of each reagent under reaction conditions which are appropriate to the compound of general formula (II), for example, by the addition of an alkylating reagent and a coordinating reagent to the compound of general formula (II) first and followed by the addition of a base to the resulting mixture obtained.
  • the present invention provides several advantages in respect that the extremely low-temperature reaction (about -78°C), which is an indispensable step in the conventional procedure and additionally unsuitable for the industrial large-scale manufacturing, can be avoided by selection of a suitable base and coordinating reagent, and a compound having the general formula (Ia) can be synthesized in a high yield even at an industrially applicable temperature, for example, at a temperature ranging from - 25°C to 10°C.
  • the present process of the present invention is superior to the prior art in respect that the invented procedure is on an industrially utilizable level.
  • the alkylating agent employed in the above reaction is not particularly restricted provided that it can be generally used in the alkylation of ester-enolates, and can be, for example, methyl chloride, methyl bromide, methyl iodide, methyl methanesusulfonate, methyl trifluoromethanesulfonate, methyl p-toluenesulfonate, dimethyl sulfate, ethyl chloride, ethyl bromide, ethyl iodide, ethyl methanesusulfonate, ethyl trifluoromethanesulfonate, ethyl p-toluenesulfonate, diethyl sulfate, propyl chloride, propyl bromide, propyl iodide, propyl methanesusulfonate, propyl trifluoromethanesulfonate, propyl
  • the coordinating reagents employed in the above reactions can be, for example, a urea such as 1,3-diinethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU) or 1,3-dimethyl-2-imidazolidinone (DMI); an amide such as 1-methyl-2-pyrrolidinone (NMP), N,N-dimethylacetamide (DMAc) or N,N-dimethylformamide (DMF); a sulfoxide such as dimethyl sulfoxide (DMSO); a crown ether such as 12-crown-4, 15-crown-5 or 18-crown-6; or an ethylene glycol such as diethylene glycol dimethyl ether (diglyme), triethylene glycol dimethyl ether (triglyme), tetraethylene glycol dimethyl ether (tetraglyme) or polyethylene glycol, and is preferably DMPU, DMI, NMP, DMF, DMSO, t
  • the base employed in the above reaction is not particularly restricted provided that it is a low-nucleophilic base, and can be, for example, an alkali metal amide such as lithium bis(trimethylsilyl)amide (LHMDS), lithium diisopropylamide (LDA), sodium bis(trimethylsilyl)amide (SHMDS) or potassium bis(trimethylsilyl)amide (KHMDS); or an alkali-metal alkoxide such as sodium t-butoxide or potassium t-butoxide, and is preferably potassium t-butoxide.
  • an alkali metal amide such as lithium bis(trimethylsilyl)amide (LHMDS), lithium diisopropylamide (LDA), sodium bis(trimethylsilyl)amide (SHMDS) or potassium bis(trimethylsilyl)amide (KHMDS)
  • an alkali-metal alkoxide such as sodium t-butoxide or potassium t-butoxide, and is preferably potassium t-butoxide.
  • the inert solvent employed in the above reaction is not particularly restricted provided that it has no adverse effect on the reaction, and can be, for example, an ether such as tetrahydrofuran, diethyl ether, t-butylmethyl ether, 1,4-dioxane or dimethoxyethane; an aromatic hydrocarbon such as toluene or xylene; an aliphatic hydrocarbon such as hexane or heptane; or a mixed solvent thereof, and is preferably an ether, and more preferably tetrahydrofuran or methoxyethane.
  • an ether such as tetrahydrofuran, diethyl ether, t-butylmethyl ether, 1,4-dioxane or dimethoxyethane
  • an aromatic hydrocarbon such as toluene or xylene
  • an aliphatic hydrocarbon such as hexane or heptane
  • a mixed solvent thereof is preferably
  • the reaction temperature employed in the above reaction is different depending on the starting material, the reagent used and the sort of solvent, but is generally between - 100°C and 30°C, preferably between -80°C and 10°C, and most preferably between - 25°C and 10°C.
  • the reaction time employed in the above reaction is different depending on the reaction temperature, the starting material, the reagent and the sort of solvent employed, but is generally from 5 minutes to 24 hours, and preferably from 30 minutes to 5 hours.
  • the desired compound of this reaction can be isolated from the reaction mixture by conventional treatments.
  • the desired compound can be isolated, for example, by neutralization of the reaction mixture, if necessary, or filtration of the reaction mixture when insoluble material is present in the reaction mixture, extraction of the neutralized solution or the filtrate with an organic solvent immiscible with water such as toluene, washing the resulting organic layer with water, separation of the organic layer containing the desired compound, and then evaporation of the organic solvent under reduced pressure.
  • the product thus obtained can be further isolated and purified by conventional treatments, for example, by recrystallization or reprecipitation, or by conventional procedures generally used in the isolation and purification of organic compounds (for example, absorption column chromatography using a carrier such as silica gel, alumina or Florisil consisting of magnesium and silica gel;partition column chromatography using Sephadex LH-20 (product of Pharmacia Co., Ltd.), Amberlite XAD-11 (product of Rohm & Hass Co., Ltd.) or Diaion HP-20 (product of Mitsubishi Chemicals Co., Ltd.); ion exchange chromatography; or normal phase or reversed phase column chromatography using silica gel or alkylated silica gel, and preferably by column chromatography using silica gel).
  • a carrier such as silica gel, alumina or Florisil consisting of magnesium and silica gel
  • Partition column chromatography using Sephadex LH-20 product of Pharmacia Co., Ltd.
  • Amberlite XAD-11 product
  • Step B1 is a process for the preparation of a compound having the general formula (Ib).
  • R, R 2 , R 3 and R 4 have the same meanings as those indicated hereinbefore.
  • a compound having the general formula (Ib) can be prepared by reacting a compound having the general formula (Ia) with a reducing agent in an inert solvent.
  • the reducing agent employed in the above reaction is not particularly restricted provided that it is generally used in the reduction of an ester to a primary alcohol, and can be, for example, a metal salt ofborohydride such as lithium borohydride, sodium borohydride or potassium borohydride; a metal salt of aluminum hydride such as lithium aluminum hydride, sodium aluminum hydride or sodium bis(2-methoxyethoxy)aluminum hydride; or a metal hydride such as isobutylaluminum hydride, and these reducing agents described above can be also used as a combination with a lithium halogenide such as lithium chloride, lithium bromide or lithium iodide, or a lanthanide halogenide such as cerium trichloride, samarium trichloride or europium trichloride, and is preferably lithium borohydride, sodium borohydride, potassium borohydride or sodium bis(2-methoxyethoxy)aluminum hydride, or
  • the inert solvent employed in the above reaction is different depending on the sort of reagents used, but is not particularly restricted provided that it has no adverse effect on the reaction, and can be, for example, an aliphatic hydrocarbon such as hexane or heptane; an aromatic hydrocarbon such as toluene or xylene; a halogenated hydrocarbon such as dichloromethane or 1,2-dichloroethane; an ether such as tetrahydrofuran, diethyl ether or t-butyl methyl ether; an alcohol such as methanol, ethanol or n-propanol; or a mixed solvent of these solvents, and is preferably an aromatic hydrocarbon, an ether or an alcohol, or a mixed solvent of these solvents, and more preferably tetrahydrofuran or toluene, or a mixed solvent of these solvents.
  • an aliphatic hydrocarbon such as hexane or heptane
  • aromatic hydrocarbon such
  • the reaction temperature employed in the above reaction is different depending on the starting material, the reagent used and the sort of solvent, but is generally between - 80°C and 120°C, and preferably between -20°C and 50°C.
  • the reaction time employed in the above reaction is different depending on the reaction temperature, the starting material, the reagent used and the sort of solvent employed, but is generally from 5 minutes to 48 hours, and preferably from 30 minutes to 10 hours.
  • the desired compound of this reaction can be isolated from the reaction mixture and purified in the same manner as those described in the Method A.
  • Step C1 is a process for the preparation of a compound having the general formula (Ic).
  • R 2 , R 3 and R 4 have the same meanings as those indicated hereinbefore.
  • a compound having the general formula (Ic) can be prepared by reacting a compound having the general formula (Ib) with an oxidizing agent in an inert solvent.
  • the oxidizing agent employed in the above reaction is not particularly restricted provided that it is generally used in the oxidation of a primary alcohol to a corresponding aldehyde, and can be, for example, a chromic acid compound such as potassium chromate, chromic acid-sulfuric acid complex or chromic acid-pyridine complex; a combination of a co-oxidizing agent such as a salt of hypochlorous acid, a salt of bromous acid, N-chlorosuccinimide or molecular oxygen and a catalytic amount of 2,2,6,6-tetramethylpiperidinooxy, free radical (TEMPO) and another salt; a reagent used for DMSO oxidation (complex of dimethylsufoxide and dicyclohexylcarbodiimide, oxalyl chloride, acetic anhydride or phosphorus pentoxide, or a complex of pyridine-sulfuric anhydride); a combination of a transition metal catalyst such as a
  • the inert solvent employed in the above reaction is different depending on the sort of reagents used, but is not particularly restricted provided that it has no adverse effect on the reaction, and when the combination of a salt of hypochlorous acid, TEMPO and other salts is used as the oxidizing agent, the inert solvent employed can be an aliphatic hydrocarbon such as hexane or heptane; an aromatic hydrocarbon such as toluene or xylene; a halogenated hydrocarbon such as dichloromethane or 1,2-dichloroethane; an ester such as ethyl acetate or butyl acetate; or a mixed solvent of the solvents described above and water, and is preferably a mixed solvent of toluene and water.
  • an aliphatic hydrocarbon such as hexane or heptane
  • an aromatic hydrocarbon such as toluene or xylene
  • a halogenated hydrocarbon such as dichloromethane or 1,2-
  • the reaction temperature employed in the above reaction is different depending on the starting material, the reagent used and the sort of solvent, but is generally between - 50°C and 100°C, and preferably between -10°C and 20°C.
  • the reaction time employed in the above reaction is different depending on the reaction temperature, the starting material, the reagent used and the sort of solvent employed, but is generally from 5 minutes to 48 hours, and preferably from 30 minutes to 5 hours.
  • the desired compound of this reaction can be isolated from the reaction mixture and purified in the same manner as those described in the Method A.
  • Step D1 is an alternative procedure to Method C for the preparation of a compound having the general formula (Ic).
  • R, R 2 , R 3 and R 4 have the same meanings as those indicated hereinbefore.
  • a compound having the general formula (Ic) can be prepared in one step by reacting a compound having the general formula (Ia) with a reducing agent in an inert solvent without passing through a compound having the general formula (Ib).
  • the reducing agent employed in the above reaction is not particularly restricted provided that it is generally used in a reduction reaction of an ester into an aldehyde, and can be, for example, a metal salt of borohydride such as lithium borohydride, sodium borohydride or potassium borohydride; a metal salt of aluminum hydride such as lithium aluminum hydride, sodium aluminum hydride or sodium bis(2-methoxyethoxy)aluminum hydride; or a metal hydride such as isobutylaluminum hydride, and these reducing agents described above can be also used as a combination with an organic amine such as pyrrolidine or morpholine, and is preferably sodium bis(2-methoxyethoxy)aluminum hydride or a combination thereof with an organic amine, and more preferably sodium bis(2-methoxyethoxy)aluminum hydride.
  • borohydride such as lithium borohydride, sodium borohydride or potassium borohydride
  • aluminum hydride
  • the inert solvent employed in the above reaction is not particularly restricted provided that it has no adverse effect on the reaction, and can be, for example, an aliphatic hydrocarbon such as hexane or heptane; an aromatic hydrocarbon such as toluene or xylene; or a halogenated hydrocarbon such as dichloromethane or 1,2-dichloroethane, and is preferably toluene.
  • the reaction temperature employed in the above reaction is different depending on the starting material, the reagent used and the sort of solvent, but is generally between - 100°C and 50°C, and preferably between -50°C and 20°C.
  • the reaction time employed in the above reaction is different depending on the reaction temperature, the starting material, the reagent used and the sort of solvent employed, but is generally from 5 minutes to 48 hours, and preferably from 30 minutes to 10 hours.
  • the desired compound of this reaction can be isolated from the reaction mixture and purified in the same manner as those described in the Method A.
  • the method E is a method for the preparation of compounds having the general formulae (Id') and (Id).
  • R, R 2 , R 3 , R 4 , W, X and Y have the same meanings as those indicated hereinbefore.
  • Step E1 is a process for the preparation of a compound having the general formula (Id') by reacting a compound having the general formula (Ic) with a compound having the general formula (IV) in the presence of a base in an inert solvent.
  • the base employed in the above reaction is not particularly restricted provided that it is generally used in the Wittig reaction, and can be, for example, an alkali metal carbonate such as sodium carbonate, potassium carbonate or cesium carbonate; an alkali metal hydride such as lithium hydride or sodium hydride; an alkali metal hydroxide such as sodium hydroxide, potassium hydroxide, barium hydroxide or lithium hydroxide; an alkali metal alkoxide such as sodium methoxide, sodium ethoxide, sodium tert-butoxide or potassium tert-butoxide; an organic base such as 1,8-diazabicyclo[5.4.0]undec-7-ene; an alkyllithium such as butyllithium or an alkylmagnesium halide such as butylmagnesium bromide; an alkali metal amide such as lithium diisopropylamide, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide or potassium bis(trimethyls
  • the inert solvent employed in the above reaction is not particularly restricted provided that it has no adverse effect on the reaction, and can be, for example, an ether such as tetrahydrofuran, diethyl ether, t-butylmethyl ether; a urea such as 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone or 1,3-dimethyl-2-imidazolidinone; an amide such as 1-methyl-2-pyrrolidinone, N,N-dimethylacetamide or N,N-dimethylformamide; a sulfoxide such as dimethyl sulfoxide; or an alkylnitrile such as acetonitrile, and preferably a urea or an amide, and more preferably N,N-dimethylformamide.
  • an ether such as tetrahydrofuran, diethyl ether, t-butylmethyl ether
  • a urea such as 1,3-
  • the reaction temperature employed in the above reaction is different depending on the starting material, the reagent used and the sort of solvent, but is generally between - 80°C and 30°C, and preferably between -20°C and 10°C.
  • the reaction time employed in the above reaction is different depending on the reaction temperature, the starting material, the reagent used and the sort of solvent employed, but is generally from 5 minutes to 48 hours, and preferably from 30 minutes to 5 hours.
  • the desired compound of this reaction can be isolated from the reaction mixture and purified in the same manner as those described in the Method A.
  • Step E2 is a process for the preparation of a compound having the general formula (Id) by reacting a compound having the general formula (Id') with a reducing agent in an inert solvent.
  • the reduction reaction is preferably carried out with a metal catalyst in a hydrogen atmosphere.
  • the metal catalyst employed in the above reaction is not particularly restricted provided that it can generally be used for catalytic reduction, and can be, for example, a heterogeneous palladium-type catalyst such as palladium-charcoal, palladium-alumina or palladium-zeolite; a nickel-type catalyst such as Raney nickel; a platinum catalyst such as platinum oxide or platinum-charcoal; a rhodium-type catalyst such as rhodium-aluminum oxide, rhodium-charcoal or triphenylphosphine- rhodium chloride; or a noble metal catalyst other than the catalysts described above such as ruthenium-charcoal, and preferably a heterogeneous palladium-type catalyst such as palladium-charcoal, palladium-alumina or palladium-zeolite.
  • a heterogeneous palladium-type catalyst such as palladium-charcoal, palladium-alumina or palladium-zeolite
  • the pressure of hydrogen employed in the above reaction is generally between 0.1 and 50 atmospheric pressures, and preferably between 1 and 10 atmospheric pressures.
  • the inert solvent employed in the above reaction is not particularly restricted provided that it has no adverse effect on the reaction, and can be, for example, an aliphatic hydrocarbon such as hexane or heptane; an aromatic hydrocarbon such as toluene or xylene; a halogenated hydrocarbon such as dichloromethane or 1,2-dichloroethane; an ester such as ethyl acetate or butyl acetate; an ether such as tetrahydrofuran, diethyl ether or t-butyl methyl ether; an amide such as 1-methyl-2-pyrrolidinone, N,N-dimethylformamide or N,N-dimethylacetamide; an alcohol such as methanol, ethanol or n-propanol; an organic acid such as formic acid or acetic acid; an aqueous inorganic acid solution such as aqueous hydrochloric acid solution or aqueous sulfuric acid solution; or water; or
  • the reaction temperature employed in the above reaction is different depending on the starting material, the reagent used and the sort of solvent, but is generally between - 20°C and 100°C, and preferably between 0°C and 50°C.
  • the reaction time employed in the above reaction is different depending on the reaction temperature, the starting material, the reagent used and the sort of solvent employed, but is generally from 5 minutes to 48 hours, and preferably from 30 minutes to 5 hours.
  • the desired compound of this reaction can be isolated from the reaction mixture and purified in the same manner as those described in the Method A.
  • Method F is an alternative procedure to Method E for the preparation of a compound having the general formula (Id).
  • Step F1 is a process for the preparation of a compound having the general formula (V') and achieved by reacting a compound having the general formula (Ib) with a halogenating agent or a sulfonylating agent in the presence or absence of a base in an inert solvent.
  • the halogenating agent employed in the above reaction is not particularly restricted provided that it is generally used for the halogenation of a primary alcohol, and can be, for example, oxalyl chloride; a thionyl halide such as thionyl chloride or thionyl bromide; a phosphorus trihalogenide such as phosphorus trichloride or phosphorus tribromide; a phosphorus pentahalide such as phosphorus pentachloride or phosphorus pentabromide; a phosphorus oxyhalide such as phosphorus oxychloride or phosphorus oxybromide; a Vilsmeier type reagent such N,N-dimethylchloroforminium chloride or N,N-dimethylbromoforminium bromide; a combination of a phosphine such as triphenylphosphine and a halogen atom or a tetrahalogenated methane; or a
  • the sulfonylating agent employed in the above reaction is not particularly restricted provided that it is generally used for sulfonylation reaction, and can be, for example, a sulfonyl halide such as methanesulfonyl chloride or p-toluenesulfonyl chloride, or a sulfonic anhydride, and is preferably methanesulfonyl chloride or p-toluenesulfonyl chloride.
  • a sulfonyl halide such as methanesulfonyl chloride or p-toluenesulfonyl chloride
  • a sulfonic anhydride is preferably methanesulfonyl chloride or p-toluenesulfonyl chloride.
  • the base employed in the above reaction is different depending on the sort of reagents used, but is not particularly restricted, and can be, for example, an organic base such as imidazole, pyridine, triethylamine or N-methylimidazole, and is preferably as imidazole, pyridine or triethylamine.
  • the inert solvent employed in the above reaction is different depending on the sort of reagents used, but is not particularly restricted provided that it has no adverse effect on the reaction, and can be, for example, an aliphatic hydrocarbon such as hexane or heptane; an aromatic hydrocarbon such as toluene or xylene; a halogenated hydrocarbon such as dichloromethane or 1,2-dichloroethane; an ester such as ethyl acetate or butyl acetate; an ether such as tetrahydrofuran, diethyl ether or t-butyl methyl ether; or an amide such as 1-methyl-2-pyrrolidinone, N,N-dimethylformamide or N,N-dimethylacetamide, and is preferably toluene.
  • an aliphatic hydrocarbon such as hexane or heptane
  • aromatic hydrocarbon such as toluene or xylene
  • the reaction temperature employed in the above reaction is different depending on the starting material, the reagent used and the sort of solvent, but is generally between - 20°C and 120°C, and preferably between 0°C and 80°C.
  • the reaction time employed in the above reaction is different depending on the reaction temperature, the starting material, the reagent used for the reaction and the sort of solvent employed, but is generally from 5 minutes to 48 hours, and preferably from 1 hour to 10 hours.
  • the compound having the general formula (V') in which Z is a halogen group can be prepared by reacting a compound having the general formula (V') in which Z is a sulfonyl group with a halogenating agent in an inert solvent.
  • the halogenating agent employed in the above reaction is not particularly restricted provided that it is generally used for halogenation of a compound in which a moiety of primary alcohol is sulfonylated, and can be, for example, a halogenated metal such as lithium chloride, lithium bromide, lithium bromide, sodium bromide, sodium iodide, potassium iodide, zinc chloride, zinc bromide or zinc iodide, and is preferably sodium iodide or potassium iodide.
  • a halogenated metal such as lithium chloride, lithium bromide, lithium bromide, sodium bromide, sodium iodide, potassium iodide, zinc chloride, zinc bromide or zinc iodide, and is preferably sodium iodide or potassium iodide.
  • the inert solvent employed in the above reaction is not particularly restricted provided that it has no adverse effect on the reaction, and can be, for example, an ether such as tetrahydrofuran, diethyl ether or t-butyl methyl ether; an amide such as 1-methyl-2-pyrrolidinone, N,N-dimethylformamide (DMF), or N,N-dimethylacetamide; an alcohol such as methanol, ethanol or n-propanol; or a sulfoxide such as dimethyl sulfoxide, and is preferably DMF.
  • an ether such as tetrahydrofuran, diethyl ether or t-butyl methyl ether
  • an amide such as 1-methyl-2-pyrrolidinone, N,N-dimethylformamide (DMF), or N,N-dimethylacetamide
  • an alcohol such as methanol, ethanol or n-propanol
  • a sulfoxide such as di
  • the reaction temperature employed in the above reaction is different depending on the starting material, the reagent used and the sort of solvent, but is generally between - 20°C and 120°C, and preferably between 20°C and 100°C.
  • the reaction time employed in the above reaction is different depending on the reaction temperature, the starting material, the reagent used for the reaction and the sort of solvent employed, but is generally from 30 minutes to 48 hours, and preferably from 1 hour to 10 hours.
  • the desired compound of this reaction can be isolated from the reaction mixture and purified in the same manner as those described in the Method A.
  • Step F2 is a process for the preparation of a compound having the general formula (V).
  • This step is achieved by reacting a compound having the general formula (V') with a phosphine or a phosphonic acid ester in an inert solvent.
  • the phosphine employed in the above reaction is not particularly restricted provided that it is generally used for the synthesis of a phosphonium salt, and can be, for example, trimethylphosphine, triethylphosphine, tripropylphosphine, tributylphosphine or triphenylphosphine, and is preferably triphenylphosphine.
  • the phosphonic acid ester employed in the above reaction is not particularly restricted provided that it is generally used for the synthesis of the phosphonic acid ester, and can be, for example, a phosphonic acid ester indicated in the above-mentioned definition, and is preferably triethyl phosphonate.
  • the inert solvent employed in the above reaction is not particularly restricted provided that it has no adverse effect on the reaction, and can be, for example, an aliphatic hydrocarbon such as hexane or heptane; an aromatic hydrocarbon such as toluene or xylene; a halogenated hydrocarbon such as dichloromethane or 1,2-dichloroethane; an ester such as ethyl acetate or butyl acetate; an ether such as tetrahydrofuran, diethyl ether or t-butyl methyl ether; an amide such as 1-methyl-2-pyrrolidinone, N,N-dimethylformamide (DMF) or N,N-dimethylacetamide; an alcohol such as methanol, ethanol or n-propanol; a sulfoxide such as dimethyl sulfoxide; a nitrile such as acetonitrile, but depending on the reagent employed, the above reaction can be
  • the reaction temperature employed in the above reaction is different depending on the starting material, the reagent used and the sort of solvent, but is generally between - 20°C and 120°C, and preferably between 20°C and 100°C.
  • the reaction time employed in the above reaction is different depending on the reaction temperature, the starting material, the reagent used for the reaction and the sort of solvent employed, but is generally from 5 minutes to 48 hours, and preferably from 30 minutes to 10 hours.
  • the desired compound of this reaction can be isolated from the reaction mixture and purified in the same manner as those described in the Method A.
  • Step F3 is a process for the preparation of a compound having the general formula (Id') by reacting a compound having the general formula (V) with a compound having the general formula (VI) in the presence of a base in an inert solvent. Step F3 can be carried out in the same manner as that described in Step E1 of the method E.
  • Step F3 The compound having the general formula (Id') obtained in Step F3 can be converted into a compound having the general formula (Id) in the same manner as that described in Step E2 of the Method E.
  • Method G is a process for the preparation of a compound having the general formula (IV') by reacting a compound having the general formula (IV") or salt thereof with a compound having the general formula (A) in the presence of a compound having the general formula (B) in a solvent.
  • R 5 , R 6 , R 7 , V, X and Y have the same meanings as those indicated hereinbefore.
  • the amount of the compound having the general formula (A) used is generally from 0.5 to 40.0 molar equivalents of the amount of the compound having the general formula (IV") or salt thereof used, and preferably from 1.0 to 10.0 molar equivalents.
  • the amount of the compound having the general formula (B) used is generally from 0.5 to 40.0 molar equivalents of the amount of the compound having the general formula (IV") or salt thereof used, and preferably from 1.0 to 10.0 molar equivalents.
  • the reaction of this Step is generally carried out in a solvent.
  • the solvent employed in the above reaction can be, for example, an amide such as N,N-dimethylformamide, N,N-dimethylacetamide or N-methylpyrrolidone; a sulfoxide such as dimethyl sulfoxide; a halogenated hydrocarbon such as chloroform or dichloromethane; an aromatic hydrocarbon such as benzene or toluene; an aliphatic hydrocarbon such as hexane or cyclohexane; an ether such as tetrahydrofuran, dioxane, diethyl ether or dimethoxyethane; an ester such as methyl acetate or ethyl acetate; or a nitrile such as acetonitrile or propionitrile.
  • These solvents may be used in the above reaction as mixtures containing at least two of them in any ratio.
  • the solvent employed in the above reaction is preferably a mixed solvent of an aromatic hydrocarbon and a nitrile and more preferably a mixed solvent of toluene and acetonitrile.
  • the reaction temperature employed in the above reaction is generally between -80°C and 150°C, and preferably between -20°C and 50°C.
  • the reaction time employed in the above reaction is generally from 1 minute to 240 hours, and preferably from 10 minutes to 120 hours.
  • the compound having the general formula (IV') or salt thereof thus obtained can be isolated and purified by any known procedures for isolation and purification, for example, through evaporation, concentration under reduced pressure, extraction with solvent, crystallization, recrystallization, partitioning between solvent systems, chromatography and the like.
  • IR ⁇ max (Liquid Film): 3440, 2959, 2909, 2875, 1709, 1686, 1479, 1447, 1399, 1358, 1317,1281,1196,1172,1134,1112,1069,1047,960,805,759 cm -1 .
  • IR ⁇ max (KBr): 2982, 2967, 2958, 2938, 2897, 2887, 1737, 1711, 1476, 1443, 1357, 1340, 1307, 1216, 1198, 1181, 1115, 1051, 995, 950, 937 cm -1 .
  • Example 9 (i) Following the procedure mentioned in Example 9 (i), a similar reaction was carried out using (4S)-2-(2-ethylpropyl)-1,3-oxazolidine-4-carboxylic acid methyl ester (5.00 g, 24.8 mmol) synthesized according to the procedure described in Example 13(i) to afford the crude product of the title compound.
  • the crude product thus obtained was purified by chromatography on a silica gel column (eluent: a mixed solvent of ethyl acetate and hexane) to afford the pure title compound (6.52 g, yield: 87 %).
  • IR ⁇ max (KBr): 3036, 3005, 2962, 2882, 2854, 2787, 1610, 1584, 1512, 1439, 1254, 1178, 1112, 1030, 836, 740, 719, 688, 510 cm -1 .
  • IR ⁇ max (KBr): 3065, 3046, 3004, 2986, 2867, 2829, 1585, 1484, 1435, 1161, 1109, 995, 860, 754, 742, 720, 690, 516, 498 cm -1 .
  • IR ⁇ max (KBr): 3050, 3007, 2988, 2871, 2832, 2770, 1715, 1611, 1586, 1561, 1484, 1437, 1143, 1111, 1023, 996, 943, 799, 745, 732, 689, 522, 504, 485 cm -1 .
  • the present invention is useful for providing optically active 4,4-di-substituted oxazolidine derivatives and procedures for their preparation.
  • the preparation procedures of the present invention have excellent advantages in the following respects, compared with the prior art: 1) increase in yield, 2) improvement in stereoselectivity, 3) extremely low-temperature reaction which is unsuitable for industrial large-scale synthesis is not necessary, and 4) column-chromatographic purification of intermediates is not needed in any step of these synthetic processes.
  • the compounds having the general formula (Id), which are optically active 4,4-di-substituted oxazolidine derivatives encompassed in the present invention are useful as the synthetic intermediates in the preparation of optically active ⁇ , ⁇ -di-substituted ⁇ -amino acid derivatives having an excellent glutamate receptor antagonistic action or optically active ⁇ , ⁇ -di-substituted amino alcohol derivatives having new immunosuppressive action.
  • the substituted methylenephosphonium salt which is useful as a synthetic intermediate in the preparation of compounds having the general formula (Id) and various kinds of medicines can be obtained conveniently in a high yield.

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Abstract

[Subject]
To provide optically active 4,4-di-substituted oxazolidine derivatives and procedures for their preparation.
[Means to solve the subject]
An optically active 4,4-di-substituted oxazolidine derivative having the general formula (I)
Figure imga0001
 [wherein,
R1 represents a formyl group, a hydroxymethyl group, a group of formula COOR, a halogenated methyl group, a phosphonium methyl group, or the like,
R represents a C1-C6 alkyl group, or the like,
R2 represents a C1-C6 alkyl group, a C3-C10 cycloalkyl group, or the like,
R3 represents a C2-C6 alkanoyl group, a C1-C6 alkyloxycarbonyl group, or the like, and
R4 represents a C1-C6 alkyl group or a C2-C6 alkenyl group].

Description

    [Technical field of the invention]
  • The present invention relates to optically active 4,4-di-substituted oxazolidine derivatives and procedures for their preparation. The optically active 4,4-di-substituted oxazolidine derivatives of the present invention have advantage as useful synthetic intermediates in new stereoselective industrial manufacturing methods of optically active α,α-di-substituted α-amino acid derivatives and optically active α,α-di-substituted α-amino alcohol derivatives.
    • [Background of the invention]
  • As a method for the preparation of optically active α,α-di-substituted α-amino acid derivatives through optically active 4,4-di-substituted oxazolidine derivatives as a synthetic intermediate, for example, methods described by Dieter Seebach, et al. (refer to non-patent literature 1 and non-patent literature 2) and by Carlos Cativiela, et al. (refer to non-patent literature 3 and non-patent literature 4) have been known.
  • The method described by Dieter Seebach, et al., however, is an unsuitable method for industrial large-scale synthesis because of the extremely low-temperature reaction conditions needed and, additionally, the yield is low.
  • On the other hand, the method described by Carlos Cativiela, et al. is a method that includes the processes of diastereoselective alkylation using an optically active cyano ester compound and Sharpless asymmetric oxidation, but in the former process, the low yield, low stereoselectivity and numerous reaction steps are a disadvantage, and in the latter process, the use of a peroxidized compound and numerous reaction steps are a disadvantage, and these procedures are also unsuitable for industrial large-scale synthesis.
  • Furthermore, optically active 4,4-di-substituted oxazolidine derivatives have been used as a synthetic intermediate for the preparation of glutamate receptor antagonists, which are optically active α,α-di-substituted α-amino acid derivatives, and its usefulness have already been known. Glutamate receptor antagonists have been reported as effective against epilepsy, brain defects following heart pypass surgery and/or transplantation, attack, cerebral ischemia, pain, spinal cord injury, head trauma, hypoxia at birth, cardiac arrest and hypoglycemia-induced damage, anxiety, neurodegenerative diseases, Huntington's chorea, AIDS-induced dementia, eye damage, retinopathy, cognitive deficiency, Parkinson's disease, Alzheimer's disease, multiple sclerosis, or the like (refer to non-patent literature 5 to 7 and patent literature 1).
  • Additionally, several reports demonstrate that optically active α,α-di-substituted α-amino alcohol derivatives exert an immunosuppressive activity based on a novel mechanism of action (refer to non-patent literatures 8 to 10 and patent literature 2), and the optically active 4,4-di-substituted oxazolidine derivatives of the present invention are considered to be useful synthetic intermediates for the preparation of the optically active α,α-di-substituted α-amino alcohol derivatives.
  • As the manufacturing method of the substituted methylenephosphonium salt disclosed in the patent literature 2, for example, the following procedure (non-patent literature 11) has been disclosed, and compound (IV'-a) is synthesized from the known compound (IV"-a) through the compound (V-a) as the synthetic intermediate, as shown in the following reaction scheme.
    Figure imgb0001
  • However, this procedure has several disadvantages described below:
    1. (1) In Step 1, methyl iodide, which is a mutagen is used and harmful effects on operators and operational environment are a concern.
    2. (2) In Step 2, the heating condition is indispensable for the reaction to proceed, but the compound (V-a) is thermally unstable and, additionally, partially decomposed before initiation of the reaction and, consequently, low production yield and low purity of the compound (IV'-a) thus obtained are disadvantageous.
    3. (3) As Step 2 is an equilibrium reaction, it is necessary to remove out of the reaction system trimethylamine generated by the progress of the reaction for the reaction to proceed smoothly. Trimethylamine , however, is a malodorous material, and the necessity of special measures such as an amine trap is disadvantageous.
    4. (4) Additionally, in Step 2, long-period heating is needed, and an expensive manufacturing cost, when this method is applied to the industrial manufacturing, becomes a problem.
    • [Non-patent literature 1] Tetrahedron Letters, vol. 25, 2545 (1984)
    • [Non-patent literature 2] Helvetica Chimica Acta, vol. 70, 1194 (1987)
    • [Non-patent literature 3] Tetrahedron, vol. 54, 14963 (1998)
    • [Non-patent literature 4] Journal of Organic Chemistry, vol. 64, 8220 (1999)
    • [Non-patent literature 5] Bioorganic Medicinal Chemistry Letters, vol. 8, 447 (1998)
    • [Non-patent literature 6] Bioorganic Medicinal Chemistry Letters, vol. 8, 925 (1998)
    • [Non-patent literature 7] Journal of Medicinal Chemistry, vol. 41, 1641 (1998)
    • [Non-patent literature 8] Journal of Medicinal Chemistry, vol. 43, 2946 (2000)
    • [Non-patent literature 9] Tetrahedron Letters, vol. 43, 8095 (2002)
    • [Non-patent literature 10] Synthesis, 1667 (2003)
    • [Non-patent literature 11] The Journal of Organic Chemistry, vol. 52, 19 (1987)
    • [Patent literature 1] United States Patent Number 5578593 Specification
    • [Patent literature 2] Japanese Patent Publication (Kokai) Number 2003-4599
    [Disclosure of the invention] [Subject to be solved by the invention]
  • The subject of the present invention is to provide less-expensive and more efficient stereoselective procedures for the preparation of optically active α,α-di-substituted α-amino acid derivatives and optically active α,α-di-substituted α-amino alcohol derivatives. Furthermore, by providing said manufacturing procedure of the present invention, it becomes possible to perform practical mass production of glutamate receptor antagonists that are useful for therapy against epilepsy, brain deficit following epilepsy, heart bypass surgery, and transplantation of an organ, attack, ischemic brain, pain, spinal cord injury, head trauma, hypoxia at birth, cardiac failure and hypoglycemic damage, anxiety, neurodegenerative diseases, Huntington's disease, AIDS-induced dementia, eye damage, retinopathy, cognitive disorder, Parkinson's disease, Alzheimer's disease, or multiple sclerosis, or the like; or immunosuppressive agents that are useful for therapy against suppression of rejection symptoms caused by organ transplantation or skin transplantation, or for therapy against autoimmune diseases such as rheumatic arthritis, psoriasis, multiple sclerosis, inflammatory bowel disease, lupus erythematosus nephritis, glomerular nephritis, insulin resistant diabetes mellitus, atopic dermatitis, and the like.
    • [Measures to solve the subject]
  • The inventors of the present invention have diligently investigated for many years into various procedures for the preparation of α,α-di-substituted α-amino acid derivatives and optically active α,α-di-substituted α-amino alcohol derivatives in order to solve the subject described above, and discovered a synthetic procedure comprising processes through optically active 4,4-di-substituted oxazolidine derivatives shown below and furthermore a preparation procedure by which the substituted-methylenephosphonium salt which is useful as the intermediate can be obtained conveniently in high yield, and consequently, the inventors completed the present invention.
    Figure imgb0002
  • The present invention provides
    1. (1) an optically active 4,4-di-substituted oxazolidine derivative having the general formula (I)
      Figure imgb0003
       [wherein,
      • R1 represents a C1-C3 alkyl group which is substituted with one substituent selected from Substituent group A, a C2-C3 alkenyl group which is substituted with one substituent selected from Substituent group A, a halogenated methyl group, a hydroxymethyl group, a formyl group, a group of formula COOR or a phosphonium methyl group,
      • R represents a C1-C6 alkyl group, a C2-C6 alkenyl group, a phenyl group or a benzyl group,
      • R2 represents a C1-C6 alkyl group, a C3-C10 cycloalkyl group or a phenyl group,
      • R3 represents a C2-C6 alkanoyl group, a C1-C6 alkyloxycarbonyl group, a benzoyl group, a phenyloxycarbonyl group or a benzyloxycarbonyl group,
      • R4 represents a C1-C6 alkyl group or a C2-C6 alkenyl group,
        Substituent group A represents a phenyl group which may optionally be substituted with from 1 to 3 substituents selected from the group consisting of a halogen atom, a cyano group, a phenyl group, a C1-C8 alkyl group, a C1-C8 alkoxy group and a C2-C8 alkanoyl group, a thienyl group, a N-methylpyrrolyl group or a furanyl group], and preferably
    2. (2) an optically active 4,4-di-substituted oxazolidine derivative having the general formula (I) described in (1) wherein R1 represents a formyl group,
    3. (3) an optically active 4,4-di-substituted oxazolidine derivative having the general formula (I) described in (1) wherein R1 represents a hydroxymethyl group,
    4. (4) an optically active 4,4-di-substituted oxazolidine derivative having the general formula (I) described in (1) wherein R1 represents a group of formula COOR, and R represents a C1-C4 alkyl group, an allyl group, a phenyl group or a benzyl group,
    5. (5) an optically active 4,4-di-substituted oxazolidine derivative having the general formula (I) described in (1) wherein R1 represents a methoxycarbonyl group or an ethoxycarbonyl group,
    6. (6) an optically active 4,4-di-substituted oxazolidine derivative having the general formula (I) described in (1) wherein R1 represents a halogenated methyl group,
    7. (7) an optically active 4,4-di-substituted oxazolidine derivative having the general formula (I) described in (1) wherein R1 represents an iodinated methyl group,
    8. (8) an optically active 4,4-di-substituted oxazolidine derivative having the general formula (I) described in (1) wherein R1 represents a phosphonium methyl group,
    9. (9) an optically active 4,4-di-substituted oxazolidine derivative having the general formula (I) described in (1) wherein R1 represents a methyltriphenylphosphonium iodide,
    10. (10) an optically active 4,4-di-substituted oxazolidine derivative having the general formula (I) described in (1) wherein R1 represents an ethyl group or a vinyl group both of which are substituted with one substituent selected from the group consisting of a 4-bromophenyl group, a 4-iodophenyl group, a 4-octylphenyl group, a 4-heptyloxyphenyl group, a 4-octanoylphenyl group, a thienyl group and a N-methylpyrrolyl group,
    11. (11) an optically active 4,4-di-substituted oxazolidine derivative having the general formula (I) described in (1) wherein R1 represents an ethyl group or a vinyl group both of which are substituted with a N-methylpyrrolyl group,
    12. (12) an optically active 4,4-di-substituted oxazolidine derivative having the general formula (I) described in any one of (1) to (11) wherein R2 represents an isopropyl group, a t-butyl group, a diethylmethyl group, a cyclohexyl group or an adamantyl group,
    13. (13) an optically active 4,4-di-substituted oxazolidine derivative having the general formula (I) described in any one of (1) to (11) wherein R2 represents a t-butyl group,
    14. (14) an optically active 4,4-di-substituted oxazolidine derivative having the general formula (I) described in any one of (1) to (13) wherein R3 represents an acetyl group, a methoxycarbonyl group, an ethoxycarbonyl group, a t-butoxycarbonyl group, a phenyloxycarbonyl group or a benzyloxycarbonyl group,
    15. (15) an optically active 4,4-di-substituted oxazolidine derivative having the general formula (I) described in any one of (1) to (13) wherein R3 represents a methoxycarbonyl group,
    16. (16) an optically active 4,4-di-substituted oxazolidine derivative having the general formula (I) described in any one of (1) to (15) wherein R4 represents a methyl group, and
    17. (17) any one of optically active 4,4-di-substituted oxazolidine derivatives having the general formula (I) according to (1) selected from following compounds:
      • 2-t-butyl-4-methyl-1,3-oxazolidine-3,4-dicarboxylic acid 3-t-butyl ester 4-methyl ester,
      • 2-t-butyl-4-methyl-1,3-oxazolidine-3,4-dicarboxylic acid 3-benzyl ester 4-methyl ester,
      • 2-t-butyl-4-methyl-1,3-oxazolidine-3,4-dicarboxylic acid dimethyl ester,
      • 2-t-butyl-4-methyl-1,3-oxazolidine-3,4-dicarboxylic acid 3-ethyl ester 4-methyl ester,
      • 3-acetyl-2-t-butyl-4-methyl-1,3-oxazolidine-4-carboxylic acid methyl ester,
      • 2-t-butyl-4-methyl-1,3-oxazolidine-3,4-dicarboxylic acid 3-phenyl ester 4-methyl ester,
      • 3-benzoyl-2-t-butyl-4-methyl-1,3-oxazolidine-4-carboxylic acid methyl ester,
      • 2-t-butyl-4-hydroxymethyl-4-methyl-1,3-oxazolidine-3-carboxylic acid t-butyl ester,
      • 2-t-butyl-4-hydroxymethyl-4-methyl-1,3-oxazolidine-3-carboxylic acid benzyl ester,
      • 2-t-butyl-4-hydroxymethyl-4-methyl-1,3-oxazolidine-3-carboxylic acid methyl ester,
      • 2-t-butyl-4-hydroxymethyl-4-methyl-1,3-oxazolidine-3-carboxylic acid ethyl ester,
      • (3-acetyl-2-t-butyl-4-methyl-1,3-oxazolidin-4-yl)methanol,
      • 2-t-butyl-4-hydroxymethyl-4-methyl-1,3-oxazolidine-3-carboxylic acid phenyl ester,
      • (3-benzoyl-2-t-butyl-4-methyl-1,3-oxazolidin-4-yl)methanol,
      • 2-t-butyl-4-formyl-4-methyl-1,3-oxazolidine-3-carboxylic acid t-butyl ester,
      • 2-t-butyl-4-formyl-4-methyl-1,3-oxazolidine-3-carboxylic acid benzyl ester,
      • 2-t-butyl-4-formyl-4-methyl-1,3-oxazolidine-3-carboxylic acid methyl ester,
      • 2-t-butyl-4-formyl-4-methyl-1,3-oxazolidine-3-carboxylic acid ethyl ester,
      • 3-acetyl-2-t-butyl-4-methyl-1,3-oxazolidine-4-carbaldehyde,
      • 2-t-butyl-4-formyl-4-methyl-1,3-oxazolidine-3-carboxylic acid phenyl ester,
      • 3-benzoyl-2-t-butyl-4-methyl-1,3-oxazolidine-4-carbaldehyde,
      • 2-t-butyl-4-methyl-4-[2-(1-methyl-1H-pyrro1-2-yl)ethyl]-1,3-oxazolidine-3-carboxylic acid t-butyl ester,
      • 2-t-butyl-4-methyl-4-[2-(1-methyl-1H-pyrrol-2-yl)ethyl]-1,3-oxazolidine-3-carboxylic acid benzyl ester,
      • 2-t-butyl-4-methyl-4-[2-(1-methyl-1H-pyrrol-2-yl)ethyl]-1,3-oxazolidine-3-carboxylic acid methyl ester,
      • 2-t-butyl-4-methyl-4-[2-(1-methyl-1H-pyrrol-2-yl)ethyl]-1,3-oxazolidine-3-carboxylic acid phenyl ester,
      • 2-t-butyl-4-methyl-4-[2-(1-methyl-1H-pyrrol-2-yl)ethyl]-1,3-oxazolidine-3-carboxylic acid ethyl ester,
      • 3-acetyl-2-t-butyl-4-methyl-4-[2-(1-methyl-1H-pyrrol-2-yl)ethyl]-1,3-oxazolidine, and
      • 3-benzoyl-2-t-butyl-4-methyl-4-[2-(1-methyl-1H-pyrrol-2-yl)ethyl]-1,3-oxazolidine.

      Furthermore, the present invention provides
    18. (18) a procedure for the preparation of a compound having the general formula (Ia) shown below by reacting a compound having the general formula (II) shown below with a compound having the general formula (III) in the presence of a base and a coordinating reagent in the presence or absence of a solvent,
      Figure imgb0004
       [wherein,
      • R represents a C1-C6 alkyl group, a C2-C6 alkenyl group, a phenyl group or a benzyl group,
      • R2 represents a C1-C6 alkyl group, a C3-C10 cycloalkyl group or a phenyl group,
      • R3 represents a C2-C6 alkanoyl group, a C1-C6 alkyloxycarbonyl group, a benzoyl group, a phenyloxycarbonyl group or a benzyloxycarbonyl group]

                R4-Z     (III)

        [wherein,
      • R4 represents a C1-C6 alkyl group or a C2-C6 alkenyl group,
      • Z represents a halogen atom or a group having the general formula -O-S(O)2Rc, and
      • Rc represents a methoxyl group, a C1-C6 alkyl group which may optionally be substituted with from 1 to 3 halogen atoms or a phenyl group which may optionally be substituted with from 1 to 3 substituents selected from the group consisting of a halogen atom and a methyl group]
        Figure imgb0005
         [wherein,
      • R, R2, R3 and R4 have the same meanings as those indicated hereinbefore],
    19. (19) a procedure for the preparation of a compound having the general formula (Ia) according to (18) wherein the halogen atom represents a bromine atom or an iodine atom,
    20. (20) a procedure for the preparation of a compound having the general formula (Ia) according to any one of (18) and (19) wherein the coordinating reagent employed is one reagent or at least two reagents selected from the group consisting of DMPU, DMI, NMP, DMAc, DMF, DMSO, diglyme, triglyme and tetraglyme,
    21. (21) a procedure for the preparation of a compound having the general formula (Ia) according to any one of (18) and (19) wherein the coordinating reagent employed is triglyme or tetraglyme,
    22. (22) a procedure for the preparation of a compound having the general formula (Ia) according to any one of (18) to (21) wherein the base employed is one base or at least two bases selected from the group consisting of LHMDS, LDA, SHMDS, KHMDS and potassium t-butoxide,
    23. (23) a procedure for the preparation of a compound having the general formula (Ia) according to any one of (18) to (21) wherein the base employed is potassium t-butoxide,
    24. (24) a procedure for the preparation of a compound having the general formula (Ia) according to any one of(18) to (23) wherein the solvent employed is one solvent or at least two solvents selected from the group consisting of tetrahydrofuran, 1,3-dioxolane, 1,4-dioxane and 1,2-dimethoxyethane,
    25. (25) a procedure for the preparation of a compound having the general formula (Ia) according to any one of (18) to (23) wherein the solvent employed is tetrahydrofuran or 1,2-dimethoxyethane,
    26. (26) a procedure for the preparation of a compound having the general formula (Ia) according to any one of (18) to (25) wherein the reaction temperature is between -25°C and 10°C,
    27. (27) a procedure for the preparation of a compound having the general formula (Ia) according to any one of (18) to (26) wherein the base is added to the resulting mixture prepared by addition of the coordinating reagent, the compound having the general formula (II) and the compound having the general formula (III) to the solvent,
    28. (28) a procedure for the preparation of a compound having the general formula (Ib) shown below by reacting a compound having the general formula (Ia) shown below with a reducing reagent in a solvent,
      Figure imgb0006
       [wherein
      • R represents a C1-C6 alkyl group, a C2-C6 alkenyl group, a phenyl group or a benzyl group,
      • R2 represents a C1-C6 alkyl group, a C3-C10 cycloalkyl group or a phenyl group,
      • R3 represents a C2-C6 alkanoyl group, a C1-C6 alkyloxycarbonyl group, a benzoyl group, a phenyloxycarbonyl group or a benzyloxycarbonyl group, and
      • R4 represents a C1-C6 alkyl group or a C2-C6 alkenyl group]
        Figure imgb0007
         [wherein,
      • R2, R3 and R4 have the same meanings as those indicated hereinbefore]
    29. (29) a procedure for the preparation of a compound having the general formula (Ib) according to (28) wherein the reducing agent employed is a combination of potassium borohydride and lithium chloride,
    30. (30) a procedure for the preparation of a compound having the general formula (Ic) shown below by reacting a compound having the general formula (Ib) shown below with an oxidizing agent in a solvent,
      Figure imgb0008
       [wherein,
      • R2 represents a C1-C6 alkyl group, a C3-C10 cycloalkyl group or a phenyl group,
      • R3 represents a C2-C6 alkanoyl group, a C1-C6 alkyloxycarbonyl group, a benzoyl group, a phenyloxycarbonyl group or a benzyloxycarbonyl group, and
      • R4 represents a C1-C6 alkyl group or a C2-C6 alkenyl group]
        Figure imgb0009
         [wherein,
      • R2, R3 and R4 have the same meanings as those indicated hereinbefore]
    31. (31) a procedure for the preparation of a compound having the general formula (Ic) according to (30) wherein the oxidizing agent employed is a combination of TEMPO, sodium bromide, sodium hypochloride and sodium hydrogencarbonate,
    32. (32) a procedure for the preparation of a compound having the general formula (Ic) shown below by reacting a compound having the general formula (Ia) shown below with a reducing agent in a solvent,
      Figure imgb0010
       [wherein,
      • R represents a C1-C6 alkyl group, a C2-C6 alkenyl group, a phenyl group or a benzyl group,
      • R2 represents a C1-C6 alkyl group, a C3-C10 cycloalkyl group or a phenyl group,
      • R3 represents a C2-C6 alkanoyl group, a C1-C6 alkyloxycarbonyl group, a benzoyl group, a phenyloxycarbonyl group or a benzyloxycarbonyl group, and
      • R4 represents a C1-C6 alkyl group or a C2-C6 alkenyl group]
        Figure imgb0011
         [wherein,
      • R2, R3 and R4 have the same meanings as those indicated hereinbefore]
    33. (33) a procedure for the preparation of a compound having the general formula (Ic) according to (32) wherein the reducing agent employed is sodium bis(2-methoxyethoxy)aluminum hydride,
    34. (34) a procedure for the preparation of a compound having the general formula (Id) shown below by conducting a condensation reaction between a compound having the general formula (Ic) shown below and a compound having the general formula (IV) shown below in the presence of a base in a solvent, followed by hydrogenating the product thus obtained,
      Figure imgb0012
       [wherein,
      • R2 represents a C1-C6 alkyl group, a C3-C10 cycloalkyl group or a phenyl group,
      • R3 represents a C2-C6 alkanoyl group, a C1-C6 alkyloxycarbonyl group, a benzoyl group, a phenyloxycarbonyl group or a benzyloxycarbonyl group, and
      • R4 represents a C1-C6 alkyl group or a C2-C6 alkenyl group]
        Figure imgb0013
         [wherein,
      • W represents a phosphonium salt or a phosphonic acid ester,
      • X represents a vinylene group, a sulfur atom, a nitrogen atom substituted with a methyl group and a C1-C6 alkyl group, a nitrogen atom substituted with a silyl group, a nitrogen atom substituted with an acyl group or an oxygen atom, and
      • Y represents a hydrogen atom, a halogen atom, a cyano group, a C1-C8 alkyl group, a C1-C8 alkoxyl group or a C2-C8 alkanoyl group]
        Figure imgb0014
         [wherein,
      • R2, R3, R4, X and Y have the same meanings as those indicated hereinbefore]
    35. (35) a procedure for the preparation of a compound having the general formula (Id) according to (34) wherein W is triphenylphosphonium iodide,
    36. (36) a procedure for the preparation procedure of a compound having the general formula (Id) according to (34) or (35) wherein a base employed is potassium t-butoxide,
    37. (37) a procedure for the preparation of a compound having the general formula (Id) shown below by conducting successively a conversion of a compound having the general formula (Ib) shown into a compound having the general formula (V) shown below according to a conventional method, condensation of the product thus obtained with a compound having the general formula (VI) shown below in the presence of a base in a solvent, and the hydrogenation of the product thus obtained,
      Figure imgb0015
       [wherein,
      • R2 represents a C1-C6 alkyl group, a C3-C10 cycloalkyl group or a phenyl group,
      • R3 represents a C2-C6 alkanoyl group, a C1-C6 alkyloxycarbonyl group, a benzoyl group, a phenyloxycarbonyl group or a benzyloxycarbonyl group, and
      • R4 represents a C1-C6 alkyl group or a C2-C6 alkenyl group]
        Figure imgb0016
         [wherein,
      • R2, R3 and R4 have the same meanings as those indicated hereinbefore, and
      • W represents a phosphonium salt or a phosphonic acid ester]
        Figure imgb0017
         [wherein,
      • X represents a vinylene group, a sulfur atom, a nitrogen atom substituted with a C1-C6 alkyl group, a nitrogen atom substituted with a silyl group, a nitrogen atom substituted with an acyl group or an oxygen atom, and
      • Y represents a hydrogen atom, a halogen atom, a cyano group, a C1-C8 alkyl group, a C1-C8 alkoxyl group or a C2-C8 alkanoyl group]
        Figure imgb0018
         [wherein,
      • R2, R3, R4, X and Y have the same meanings as those indicated hereinbefore] and
    38. (38) a procedure for the preparation of a compound having the general formula (Id) according to (37) wherein W is triphenylphosphonium iodide.
      Additionally, the present invention provides
    39. (39) a procedure for the preparation of a compound having the general formula (IV') shown below which is characterized by reacting a compound having the general formula (IV") or a salt thereof with a compound having the general formula (A) in the presence of a compound having the general formula (B) in a solvent,
      Figure imgb0019
       [wherein,
      • R5 represents a C1-C6 alkyl group which may optionally be substituted with substituent(s) selected from Substituent group α or a 5- to 10-membered aromatic group which may optionally be substituted with substituent(s) selected from Substituent group α, or two R5 groups together with the nitrogen atom to which they are bound form a 4-to 8-membered nitrogen-containing heterocyclic group which may optionally be substituted with substituent(s) selected from Substituent group α,
      • X represents a vinylene group, a sulfur atom, a nitrogen atom substituted with a C1-C6 alkyl group, a nitrogen atom substituted with a silyl group, a nitrogen atom substituted with an acyl group or an oxygen atom,
      • Y represents a hydrogen atom, a halogen atom, a cyano group, a C1-C8 alkyl group, a C1-C8 alkoxyl group or a C2-C8 alkanoyl group, and
      • Substituent group α represents a halogen atom, a cyano group, a C1-C8 alkyl group, a C1-C8 alkoxyl group, a C1-C8 alkylthio group and an acyl group]
        Figure imgb0020
         [wherein,
      • R6 represents a C1-C6 alkyl group which may optionally be substituted with substituent(s) selected from Substituent group α, a C1-C6 alkoxyl group which may optionally be substituted with substituent(s) selected from Substituent group α, a 5- to 10-membered aromatic group which may optionally be substituted with substituent(s) selected from Substituent group α, or a 5- to 10-membered aromatic-oxy group which may optionally be substituted with substituent(s) selected from Substituent group α, and Substituent group α has the same meaning as that described above]

                R7-V     (B)

        [wherein,
      • R7 represents an acyl group,
      • V represents a halogen atom or a group having the general formula -O-S(O)2Rc, and
      • Rc represents a methoxyl group, a C1-C6 alkyl group which may optionally be substituted with from 1 to 3 halogen atoms or a phenyl group which may optionally be substituted with from 1 to 3 substituents selected from the group consisting of a halogen atom and a methyl group]
        Figure imgb0021
         [wherein,
      • R6, V, X and Y have the same meanings as those described above]
    40. (40) a procedure for the preparation of a compound having the general formula (IV') according to (39) wherein X represents a nitrogen atom substituted with a methyl group,
    41. (41) a procedure for the preparation of a compound having the general formula (IV') according to (39) or (40) wherein Y represents a hydrogen atom, a C1-C6 alkyl group or a C1-C6 alkoxyl group,
    42. (42) a procedure for the preparation procedure of a compound having the general formula (IV') according to any one of (39) to (41) wherein R5 represents a C1-C6 alkyl group or two R5 groups together with the nitrogen atom to which they are bound form a pyrrolidine or piperidine group,
    43. (43) a procedure for the preparation of a compound having the general formula (IV') according to any one of (39) to (42) wherein R6 represents a phenyl group,
    44. (44) a procedure for the preparation of a compound having the general formula (IV') according to any one of (39) to (43) wherein R7 represents a C1-C6 alkylcarbonyl group, and
    45. (45) a procedure for the preparation of a compound having the general formula (Id) by condensing a compound having the general formula (IV'), which is prepared by reacting a compound having the general formula (IV") or a salt thereof with a compound having the general formula (A) in the presence of a compound having the general formula (B) in a solvent, with a compound of the general formula (Ic) in the presence of a base in a solvent, followed by hydrogenation of the product thus obtained;
      Figure imgb0022
       [wherein,
      • R5 represents a C1-C6 alkyl group which may optionally be substituted with substituent(s) selected from Substituent group α or a 5- to 10-membered aromatic group which may optionally be substituted with substituent(s) selected from Substituent group α, or two R5 groups together with the nitrogen atom to which they are bound form a 4-to 8-membered nitrogen-containing heterocyclic group which may optionally be substituted with substituent(s) selected from Substituent group α,
      • X represents a vinylene group, a sulfur atom, a nitrogen atom substituted with a C1-C6 alkyl group, a nitrogen atom substituted with a silyl group, a nitrogen atom substituted with an acyl group or an oxygen atom,
      • Y represents a hydrogen atom, a halogen atom, a cyano group, a C1-C8 alkyl group, a C1-C8 alkoxyl group or a C2-C8 alkanoyl group, and
      • Substituent group α represents a halogen atom, a cyano group, a C1-C8 alkyl group, a C1-C8 alkoxyl group, a C1-C8 alkylthio group and an acyl group]
        Figure imgb0023
         [wherein,
      • R6 represents a C1-C6-alkyl group which may optionally be substituted with substituent(s) selected from Substituent group α, a C1-C6 alkoxyl group which may optionally be substituted with substituent(s) selected from Substituent group α, a 5- to 10-membered aromatic group which may optionally be substituted with substituent(s) selected from Substituent group α, or a 5- to 10-membered aromatic-oxy group which may optionally be substituted with substituent(s) selected from Substituent group α, and Substituent group α has the same meaning as that described above]

                R7-V     (B)

        [wherein,
      • R7 represents an acyl group,
      • V represents a halogen atom or a group having the general formula -O-S(O)2Rc, and
      • Rc represents a methoxyl group, a C1-C6 alkyl group which may optionally be substituted with from 1 to 3 halogen atoms or a phenyl group which may optionally be substituted with from 1 to 3 substituents selected from the group consisting of a halogen atom and a methyl group]
        Figure imgb0024
         [wherein,
      • R6, V, X and Y have the same meanings as those described above]
        Figure imgb0025
         [wherein,
      • R2 represents a C1-C6 alkyl group, a C3-C10 cycloalkyl group or a phenyl group,
      • R3 represents a C2-C6 alkanoyl group, a C1-C6 alkyloxycarbonyl group, a benzoyl group, a phenyloxycarbonyl group or a benzyloxycarbonyl group, and
      • R4 represents a C1-C6 alkyl group or a C2-C6 alkenyl group]
        Figure imgb0026
         [wherein,
      • R2, R3, R4, X and Y have the same meanings as those indicated hereinbefore].
  • In the general formula (I), the "C1-C3 alkyl group" in the definition of R1 can be, for example, a methyl, ethyl, 2-methylethyl or n-propyl group, and is preferably an ethyl group.
  • In the general formula (I), the "C2-C3 alkenyl group" in the definition of R1 can be, for example, a vinyl, 2-methylvinyl or n-propenyl group, and is preferably a vinyl group.
  • In the general formula (I), the "C1-C6 alkyl group" in the definitions of R, R2 and R4 can be, for example, a methyl, ethyl, n-propyl, i-propyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, diethylmethyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl or 2-ethylbutyl group, and is preferably a C1-C4 alkyl group, and more preferably R and R4 are a methyl group and R2 is a t-butyl group.
  • In the general formula (I), the "C2-C6 alkenyl group" in the definitions of R and R4 can be, for example, a vinyl, allyl, 1-methyl-2-propenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl, 2-ethyl-2-propenyl, 1-butenyl, 2-butenyl, 1-methyl-2-butenyl, 1-methyl-1-butenyl, 3-methyl-2-butenyl, 1-ethyl-2-butenyl, 3-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 1-ethyl-3-butenyl, 1-pentenyl, 2-pentenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-pentenyl, 1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 4-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl or 5-hexenyl group, and is preferably a C1-C4 alkenyl group and more preferably a vinyl group or an allyl group.
  • In the general formula (I), the "C3-C10 cycloalkyl group" in the definition of R2 can be, for example, a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl or adamantyl group, and is preferably a C5-C10 cycloalkyl group and more preferably a cyclohexyl group or an adamantyl group.
  • In the general formula (I), the "C2-C6 alkanoyl group" in the definition of R3 can be, for example, an acetyl, propionyl, isopropionyl, n-butanoyl, isobutanoyl, n-pentanoyl, isopentanoyl, 2-methylbutanoyl, pivaloyl, n-hexanoyl, 2-methylpentanoyl, 3-methylpentanoyl or hexanoyl group, and is preferably a C2-C4 alkanoyl group and more preferably an acetyl group.
  • In the general formula (I), the "C1-C6 alkyloxycarbonyl group" in the definition of R3 can be, for example, a methoxycarbonyl, ethoxycarbonyl, propyloxycarbonyl, n-butoxycarbonyl, t-butoxycarbonyl, pentyloxycarbonyl or hexyloxycarbonyl group, and is preferably a C1-C4 alkyloxycarbonyl group and more preferably a methoxycarbonyl group.
  • In the formulae shown above, the "halogen atom" in the definitions of Substituent groups A and Y can be, for example, a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
  • In the formulae shown above, the "C1-C8 alkyl group" in the definitions of Substituent groups A and Y can be, for example, a group shown as the "C1-C6 alkyl group" in the definitions described above, a heptyl group or an octyl group, and is preferably a C6-C8 alkyl group and more preferably an octyl group.
  • In the formulae shown above, the "C1-C8 alkoxyl group" in the definitions of Substituent groups A and Y can be, for example, a methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, s-butoxy, t-butoxy, n-pentyloxy, isopentyloxy, 2-methylbutoxy, neopentyloxy, 1-ethylpropoxy, n-hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyloxy, 1-methylpentyloxy, 3,3-dimethylbutoxy, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutoxy, 2,3-dimethylbutoxy, 2-ethylbutoxy, heptyloxy or octyloxy group, and preferably a C6-C8 alkoxyl group and more preferably a heptyloxy group.
  • In the formulae shown above, the "C2-C8 alkanoyl group" in the definitions of Substituent groups A and Y can be, for example, a group shown as the "C2-C6 alkanoyl group" in the definitions described above, a heptanoyl group or an octanoyl group, and is preferably a C6-C8 alkanoyl group and more preferably an octanoyl group.
  • In the formulae shown above, the "phosphonium salt" in the definition of W can be, for example, trimethylphosphonium chloride, trimethylphosphonium bromide, trimethylphosphonium iodide, triethylphosphonium chloride, triethylphosphonium bromide, triethylphosphonium iodide, tripropylphosphonium chloride, tripropylphosphonium bromide, tripropylphosphonium iodide, tributylphosphonium chloride, tributylphosphonium bromide, tributylphosphonium iodide, triphenylphosphonium chloride, triphenylphosphonium bromide or triphenylphosphonium iodide, and is preferably triphenylphosphonium chloride.
  • In the formulae shown above, the "phosphonic acid ester" in the definition of W can be, for example, dimethyl phosphonate, diethyl phosphonate, ditrifluoroethyl phosphonate, diphenyl phosphonate, or di-o-tolyl phosphonate, and is preferably diethyl phosphonate:
  • In the formulae shown above, the "C1-C6 alkyl group" in the definition of X can be, for example, a methyl, ethyl, n-propyl, i-propyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, diethylmethyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl or 2-ethylbutyl group, and is preferably a C1-C4 alkyl group, and more preferably a methyl group.
  • In the formulae shown above, the "silyl group" in the definition of X can be, for example, a trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, t-butyldimethylsilyl, methyldiisopropylsilyl, methyldi-t-butylsilyl, triisopropylsilyl, methyldiphenylsilyl, isopropyldiphenylsilyl, butyldiphenylsilyl or phenyldiisopropylsilyl group, and is preferably a trimethylsilyl, triethylsilyl, isopropyldimethylsilyl or t-butyldimethylsilyl group.
  • In the formulae shown above, the "acyl group" in the definition of X can be, for example, a formyl, carboxyl, carbamoyl, C1-C6 alkylcarbonyl (for example, an acetyl, butanoyl, isobutanoyl or isopentanoyl group), C1-C6 alkoxycarbonyl (for example, a methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl or t-butoxycarbonyl group), C6-C14 arylcarbonyl (for example, a benzoyl, 1-naphthoyl or 2-naphthoyl group), C6-C14 aryloxycarbonyl (for example, a phenyloxycarbonyl or naphthyloxycarbonyl group), C7-C13 aralkyloxycarbonyl (for example, a benzyloxycarbonyl or phenethyloxycarbonyl group), mono- or di-C1-C6 alkylcarbamoyl the alkyl group(s) of which may optionally be substituted with from 1 to 3 substituents selected from the group consisting of a halogen atom and a C1-C6 alkoxycarbonyl group (for example, a methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl, propylcarbamoyl or trifluoroethylcarbamoyl group), C6-C14 arylcarbamoyl (for example, a phenylcarbamoyl group), C3-C10 cycloalkylcarbamoyl (for example, a cyclopropylcarbamoyl group), C7-C13 aralkylcarbamoyl (for example, a benzylcarbamoyl group), C1-C6 alkylsulfonyl (for example, a methylsulfonyl group), C6-C14 arylsulfonyl (for example, a phenylsulfonyl group), nitrogen-containing heterocyclic-carbonyl which may optionally be substituted with a hydroxyl group (for example, a pyrrolidinylcarbonyl or piperidinocarbonyl group), C1-C6 alkylsulfinyl (for example, a methylsulfinyl group), C1-C6 alkoxycarbamoyl (for example, a methoxycarbamoyl group), aminocarbamoyl, hydroxycarbampyl or thiocarbampyl group, and is preferably a formyl, C1-C6 alkylcarbonyl, C1-C6 alkoxycarbonyl, C6-C14 arylcarbonyl, C7-C13 aralkyloxycarbonyl group and more preferably an acetyl, methoxycarbonyl, ethoxycarbonyl, benzoyl or benzyloxycarbonyl group.
  • In the formulae shown above, X is preferably a vinylene group, a sulfur atom or a nitrogen atom substituted with a C1-C6 alkyl group and more preferably a vinylene group, a sulfur atom or a nitrogen atom substituted with a methyl group.
  • In the formulae shown above, Y is preferably a hydrogen atom, a halogen atom, a C1-C8 alkyl group, a C1-C8 alkoxyl group or a C2-C8 alkanoyl group and more preferably a hydrogen atom, a halogen atom, a methyl group, an octyl group, a methoxyl group or a heptyloxy group.
  • The definition of each substituent of compounds having general formulae (IV'), (IV"), (A) and (B) of the present invention is described in detail below.
  • The "C1-C6 alkyl group" of the "C1-C6 alkyl group which may optionally be substituted with substituent(s) selected from Substituent group α" in the definitions of R5 can be, for example, a methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl or 2-ethylbutyl group, and is preferably a methyl, ethyl, propyl, isopropyl, butyl or isobutyl group, and more preferably a methyl or ethyl group.
  • The "which may optionally be substituted with substituent(s) selected from Substituent group α" of the "C1-C6 alkyl group which may optionally be substituted with substituent(s) selected from Substituent group α" described above means that substitutable positions of said C1-C6 alkyl group may optionally be substituted with from 1 to 3 substituents selected from Substituent group α.
  • The "5- to 10-membered aromatic ring" of the "5- to 10-membered aromatic group which may optionally be substituted with substituent(s) selected from Substituent group α " in the definition of R5 shown above is, for example, a 5- to 10-membered aromatic hydrocarbon ring or a 5- to 10-membered aromatic heterocyclic ring. A 5- to 10-membered aromatic hydrocarbon ring is preferably a benzene ring or a naphthalene ring, and more preferably a benzene ring. On the other hand, a 5- to 10-membered aromatic heterocyclic ring is preferably a 5- to 10-membered aromatic heterocyclic ring which contains 1 to 4 heteroatoms selected from the group consisting of an oxygen, sulfur and nitrogen atom in addition to the carbon atoms as the ring-composing atoms, and is, for example, furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, imidazole, pyrazole, 1,2,3-oxadiazole, furazan, 1,2,3-thiadiazole, 1,2,3-triazole, pyridine, pyridazine, pyrimidine, triazine, benzofuran, isobenzofuran, benzo[b]thiophene, indole, isoindole, 1H-indazole, benzimidazole, benzoxazole, 1,2-benzisoxazole, bonzothiazole, 1,2-benzoisothiazole, 1H-benzotriazole, quinoline or isoquinoline, and more preferably furan or thiophene.
  • The "4- to 8-membered nitrogen-containing heterocyclic group" of the " 4- to 8-membered nitrogen-containing heterocyclic group which may optionally be substituted with substituent(s) selected from Substituent group α" is, for example, azetidine, pyrrolidine, piperidine, azepan, morpholine or piperazine, and preferably pyrrolidine or piperidine.
  • The definition of each substituent of the "Substituent group α" is described below.
  • The "halogen atom" is, for example, a fluorine, chlorine, bromine or iodine atom.
  • The "C1-C8 alkyl group" is, for example, a methyl, ethyl, n-propyl, i-propyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, heptyl or octyl group.
  • The "C1-C8 alkoxyl group" is a group wherein a terminal of the "C1-C8 alkyl group" shown above is bound to an oxygen atom.
  • The "C1-C8 alkylthio group" is a group wherein a terminal of the "C1-C8 alkyl group" shown above is bound to a sulfur atom.
  • The "acyl group" can be, for example, a group of formula -COR3', -CO2R3', -SO2R3', -SOR3', -PO3R3'R4', -CO-NR3aR4a or-CS-NR3aR4a [wherein, R3' and R4' are the same or different and each represents a hydrogen atom, a hydrocarbon group or a heterocyclic group and R3a and R4a groups are the same or different and each represents a hydrogen atom, a hydrocarbon group or a heterocyclic group, or R3a and R4a groups together with an adjacent nitrogen atom may form a nitrogen-containing heterocyclic ring].
  • The "hydrocarbon group" described for R3', R4', R3a or R4a is a "C1-C6 alkyl group", a "C3-C6 cycloalkyl group", a "C6-C10 aryl group" or a "C7-C13 aralkyl group".
  • The "nitrogen-containing heterocyclic ring" formed by R3a and R4a groups together with an adjacent nitrogen atom is a 5- to 7-membered nitrogen-containing heterocyclic ring which may contain at least one nitrogen atom and 1 or 2 heteroatoms selected from the group consisting of an oxygen, sulfur and nitrogen atom in addition to the carbon atoms as the ring-composing atoms, and is preferably pyrrolidine, imidazolidine, pyrazolidine, piperidine, piperazine, morpholine or thiomorpholine.
  • The preferred "acyl group" can be, for example, a formyl, carboxyl, carbamoyl, C1-C6 alkylcarbonyl (for example, an acetyl, butanoyl, isobutanoyl or isopentanoyl group), C1-C6 alkoxycarbonyl (for example, a methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl or t-butoxycarbonyl group), C6-C14 arylcarbonyl (for example, a benzoyl, 1-naphthoyl or 2-naphthoyl group), C6-C14 aryloxycarbonyl (for example, a phenyloxycarbonyl or naphthyloxycarbonyl group), C7-C13 aralkyloxycarbonyl (for example, a benzyloxycarbonyl or phenethyloxycarbonyl group), mono- or di-C1-C6 alkylcarbamoyl the alkyl group(s) of which may optionally be substituted with from 1 to 3 substituents selected from the group consisting of a halogen atom and a C1-C6 alkoxycarbonyl group (for example, a methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl, propylcarbamoyl or trifluoroethylcarbamoyl group), C6-C14 arylcarbamoyl (for example, a phenylcarbamoyl group), C3-C10 cycloalkylcarbamoyl (for example, a cyclopropylcarbamoyl group), C7-C13 aralkylcarbamoyl (for example, a benzylcarbamoyl group), C1-C6 alkylsulfonyl (for example, a methylsulfonyl group), C6-C14 arylsulfonyl (for example, a phenylsulfonyl group), nitrogen-containing heterocyclic-carbonyl which may optionally be substituted with a hydroxyl group (for example, a pyrrolidinylcarbonyl or piperidinocarbonyl group), C1-C6 alkylsulfinyl (for example, a methylsulfinyl group), C1-C6 alkoxycarbamoyl (for example, a methoxycarbamoyl group), aminocarbamoyl, hydroxycarbamoyl or thiocarbamopyl group.
  • The "C1-C6 alkyl group" of the "C1-C6 alkyl group which may optionally be substituted with substituent(s) selected from Substituent group α" and the "5- to 10-membered aromatic group" of the "5- to 10-membered aromatic group which may optionally be substituted with substituent(s) selected from Substituent group α" in the definition of R6 described above have the same meanings as those indicated in the definition of R5 described above.
  • The "C1-C6 alkoxyl group which may optionally be substituted with substituent(s) selected from Substituent group α" in the definition of R6 described above is a group wherein a terminal of the "C1-C6 alkyl group which may optionally be substituted with substituent(s) selected from Substituent group α" in the definition of R5 described above is bound to an oxygen atom.
  • The "5- to 10-membered aromatic-oxy group which may optionally be substituted with substituent(s) selected from Substituent group α" in the definition of R6 described above is a group wherein a terminal of the "5- to 10-membered aromatic group which may optionally be substituted with substituent(s) selected from Substituent group α" in the definition of R5 described above is bound to an oxygen atom.
  • The "acyl group" in the definition of R7 described above has the same meaning as the "acyl group" indicated in the definition of Substituent group α, and is preferably a C1-C6 alkylcarbonyl group (for example, an acetyl, butanoyl or isobutanoyl group).
  • The "C1-C6 alkyl group which may optionally be substituted with from 1 to 3 halogen atoms" in the definition of Rc described above can be, for example, a fluoromethyl, difluoromethyl, trifluoromethyl, difluoroethyl or trifluoroethyl group, and preferably a trifluoromethyl group.
  • The "phenyl group which may optionally be substituted with from 1 to 3 substituents selected from the group consisting of a halogen atom and a methyl group" in the definition of Rc described above can be, for example, a 4-fluorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 4-methylphenyl or 3,4-dimethylphenyl group, and is preferably a 4-dimethylphenyl group.
  • R5 described above is preferably a C1-C10 alkyl group which may optionally be substituted with substituent(s) selected from Substituent group α or a 4- to 8-membered nitrogen-containing heterocyclic group formed by two R5 groups together with a nitrogen atom to which they are bound which may optionally be substituted with substituent(s) selected from Substituent group α, more preferably a C1-C6 alkyl group, or pyrrolidine or piperidine formed by two R1 groups together with a nitrogen atom to which two R5 groups are bound, and still more preferably a methyl or ethyl group, or pyrrolidine or piperidine formed by two R5 groups together with a nitrogen atom to which they are bound.
  • R6 described above is preferably a C1-C6 alkyl group or a 5- to 10-membered aromatic ring group, and more preferably a phenyl group.
  • R7 described above is preferably a C1-C6 alkylcarbonyl group, and more preferably an acetyl group.
  • V described above is preferably a chlorine atom, a bromine atom or an iodine atom, and more preferably a chlorine or iodine atom.
  • X described above is preferably a vinylene group, a sulfur atom or a nitrogen atom substituted with a C1-C6 alkyl group, and more preferably a vinylene group, a sulfur atom or a nitrogen atom substituted with a methyl group.
  • Y described above is preferably a hydrogen atom, a halogen atom, a C1-C8 alkyl group, a C1-C8 alkoxyl group or C2-C8 alkanoyl group, and more preferably a hydrogen atom, a halogen atom, a methyl group, an octyl group, a methoxyl group or a heptyloxy group.
  • Substituent group α described above is preferably a halogen atom, a C1-C8 alkyl group, a C1-C8 alkoxyl group or an acyl group, more preferably a C1-C6 alkyl group or a C1-C6 alkoxyl group, and particularly preferably a methyl group or a methoxyl group.
  • When the compounds of the present invention can form salt thereof, these compounds can be used as their salts. Such a salt is, for example, an inorganic base salt, an organic base salt, an inorganic acid salt, an organic acid salt, or a basic or acidic amino acid salt.
  • The inorganic base salt is preferably an alkali metal salt such as a sodium salt, potassium salt or the like; an alkaline earth metal salt such as a calcium salt, magnesium salt or the like; an aluminum salt; an ammonium salt or the like.
  • The organic base salt is preferably a trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, diethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N-dibenzylethylenediamine salt or the like.
  • The inorganic acid salt is preferably a hydrochloride, a hydrobromide, a nitrate, a sulfate, a phosphate or the like.
  • The organic acid salt is preferably a formate, an acetate, a trifluoroacetate, a fumarate, an oxalate, a tartrate, a maleate, a citrate, a succinate, a malate, methanesulfonate, benzenesufonate, p-toluenesulfonate or the like.
  • The compounds having the general formulae (I), (Ia), (Ib), (Ic) and (Id) of the present invention have an asymmetric carbon atom in their structures, and can exist as optical isomers due to such asymmetric carbon atom. In the present invention, a single optical isomer and mixtures of optical isomers are represented as a single chemical formula (I), (Ia), (Ib), (Ic) or (Id), individually. The present invention encompasses both individual optical isomers and mixtures thereof in any ratio. In the compounds having the general formulae (I), (Ia), (Ib), (Ic) and (Id) of the present invention, an amino group is substituted on the asymmetric carbon atom, and the compounds having the R-absolute configuration are particularly desirable, but the compounds containing the S-isomer are also encompassed in the present invention.
  • When the compounds of general formulae (I), (Ia), (Ib), (Ic) and (Id) of the present invention are allowed to stand in contact with the atmosphere or recrystallized, they may absorb water or water may attach to them to form a hydrate. Such hydrates are included in the compounds having the general formulae (I), (Ia), (Ib), (Ic) and (Id) of the present invention.
  • As representative compounds of the present invention having general formulae (I), (Ia), (Ic), and (Id), the compounds shown in from Table 1 to Table 3 can be listed, but the scope of the present invention should not be limited to these compounds.
  • The meaning of the abbreviations in the following Tables is shown below.
    • Ac : acetyl group
    • Boc : t-butoxycarbonyl group
    • Bzl : benzoyl group
    • Cbz : benzyloxycarbonyl group
    • cHex : cyclohexyl group
    • Eoc : ethoxycarbonyl group
    • Et : ethyl group
    • Et2CH: dimethylmethyl group
    • HepCO : octanoyl group
    • HepO: heptyloxy group
    • iPr: isopropyl group
    • Me: methyl group
    • Moc: methoxycarbonyl group
    • Oct : octyl group
    • Ph: phenyl group
    • PhOCO :phenoxycarbonyl group
    • Pr :propyl group
    • tBu : t-butyl group
    (Table 1)
    Figure imgb0027
    Compound No. R2 R3 R4 R
    1 iPr Boc Me Me
    2 iPr Boc Me Et
    3 iPr Boc Et Me
    4 iPr Boc Et Et
    5 iPr Boc Pr Me
    6 iPr Boc Pr Et
    7 iPr Cbz Me Me
    8 iPr Cbz Me Et
    9 iPr Cbz Et Me
    10 iPr Cbz Et Et
    11 iPr Cbz Pr Me
    12 iPr Cbz Pr Et
    13 iPr Moc Me Me
    14 iPr Moc Me Et
    15 iPr Moc Et Me
    16 iPr Moc Et Et
    17 iPr Moc Pr Me
    18 iPr Moc Pr Et
    19 iPr Eoc Me Me
    20 iPr Eoc Me Et
    21 iPr Eoc Et Me
    22 iPr Eoc Et Et
    23 iPr Eoc Pr Me
    24 iPr Eoc Pr Et
    25 iPr Ac Me Me
    26 iPr Ac Me Et
    27 iPr Ac Et Me
    28 iPr Ac Et Et
    29 iPr Ac Pr Me
    30 iPr Ac Pr Et
    31 iPr PhOCO Me Me
    32 iPr PhOCO Me Et
    33 iPr PhOCO Et Me
    34 iPr PhOCO Et Et
    35 iPr PhOCO Pr Me
    36 iPr PhOCO Pr Et
    37 iPr Bzl Me Me
    38 iPr Bzl Me Et
    39 iPr Bzl Et Me
    40 iPr Bzl Et Et
    41 iPr Bzl Pr Me
    42 iPr Bzl Pr Et
    43 tBu Boc Me Me
    44 tBu Boc Me Et
    45 tBu Boc Et Me
    46 tBu Boc Et Et
    47 tBu Boc Pr Me
    48 tBu Boc Pr Et
    49 tBu Cbz Me Me
    50 tBu Cbz Me Et
    51 tBu Cbz Et Me
    52 tBu Cbz Et Et
    53 tBu Cbz Pr Me
    54 tBu Cbz Pr Et
    55 tBu Moc Me Me
    56 tBu Moc Me Et
    57 tBu Moc Et Me
    58 tBu Moc Et Et
    59 tBu Moc Pr Me
    60 tBu Moc Pr Et
    61 tBu Eoc Me Me
    62 tBu Eoc Me Et
    63 tBu Eoc Et Me
    64 tBu Eoc Et Et
    65 tBu Eoc Pr Me
    66 tBu Eoc Pr Et
    67 tBu Ac Me Me
    68 tBu Ac Me Et
    69 tBu Ac Et Me
    70 tBu Ac Et Et
    71 tBu Ac Pr Me
    72 tBu Ac Pr Et
    73 tBu PhOCO Me Me
    74 tBu PhOCO Me Et
    75 tBu PhOCO Et Me
    76 tBu PhOCO Et Et
    77 tBu PhOCO Pr Me
    78 tBu PhOCO Pr Et
    79 tBu Bzl Me Me
    80 tBu Bzl Me Et
    81 tBu Bzl Et Me
    82 tBu Bzl Et Et
    83 tBu Bzl Pr Me
    84 tBu Bzl Pr Et
    85 Et2CH Boc Me Me
    86 Et2CH Boc Me Et
    87 Et2CH Boc Et Me
    88 Et2CH Boc Et Et
    89 Et2CH Boc Pr Me
    90 Et2CH Boc Pr Et
    91 Et2CH Cbz Me Me
    92 Et2CH Cbz Me Et
    93 Et2CH Cbz Et Me
    94 Et2CH Cbz Et Et
    95 Et2CH Cbz Pr Me
    96 Et2CH Cbz Pr Et
    97 Et2CH Moc Me Me
    98 Et2CH Moc Me Et
    99 Et2CH Moc Et Me
    100 Et2CH Moc Et Et
    101 Et2CH Moc Pr Me
    102 Et2CH Moc Pr Et
    103 Et2CH Eoc Me Me
    104 Et2CH Eoc Me Et
    105 Et2CH Eoc Et Me
    106 Et2CH Eoc Et Et
    107 Et2CH Eoc Pr Me
    108 Et2CH Eoc Pr Et
    109 Et2CH Ac Me Me
    110 Et2CH Ac Me Et
    111 Et2CH Ac Et Me
    112 Et2CH Ac Et Et
    113 Et2CH Ac Pr Me
    114 Et2CH Ac Pr Et
    115 Et2CH PhOCO Me Me
    116 Et2CH PhOCO Me Et
    117 Et2CH PhOCO Et Me
    118 Et2CH PhOCO Et Et
    119 Et2CH PhOCO Pr Me
    120 Et2CH PhOCO Pr Et
    121 Et2CH Bzl Me Me
    122 Et2CH Bzl Me Et
    123 Et2CH Bzl Et Me
    124 Et2CH Bzl Et Et
    125 Et2CH Bzl Pr Me
    126 Et2CH Bzl Pr Et
    127 Ph Boc Me Me
    128 Ph Boc Me Et
    129 Ph Boc Et Me
    130 Ph Boc Et Et
    131 Ph Boc Pr Me
    132 Ph Boc Pr Et
    133 Ph Cbz Me Me
    134 Ph Cbz Me Et
    135 Ph Cbz Et Me
    136 Ph Cbz Et Et
    137 Ph Cbz Pr Me
    138 Ph Cbz Pr Et
    139 Ph Moc Me Me
    140 Ph Moc Me Et
    141 Ph Moc Et Me
    142 Ph Moc Et Et
    143 Ph Moc Pr Me
    144 Ph Moc Pr Et
    145 Ph Eoc Me Me
    146 Ph Eoc Me Et
    147 Ph Eoc Et Me
    148 Ph Eoc Et Et
    149 Ph Eoc Pr Me
    150 Ph Eoc Pr Et
    151 Ph Ac Me Me
    152 Ph Ac Me Et
    153 Ph Ac Et Me
    154 Ph Ac Et Et
    155 Ph Ac Pr Me
    156 Ph Ac Pr Et
    157 Ph PhOCO Me Me
    158 Ph PhOCO Me Et
    159 Ph PhOCO Et Me
    160 Ph PhOCO Et Et
    161 Ph PhOCO Pr Me
    162 Ph PhOCO Pr Et
    163 Ph Bzl Me Me
    164 Ph Bzl Me Et
    165 Ph Bzl Et Me
    166 Ph Bzl Et Et
    167 Ph Bzl Pr Me
    168 Ph Bzl Pr. Et
    169 cHex Boc Me Me
    170 cHex Boc Me Et
    171 cHex Boc Et Me
    172 cHex Boc Et Et
    173 cHex Boc Pr Me
    174 cHex Boc Pr Et
    175 cHex Cbz Me Me
    176 cHex Cbz Me Et
    177 cHex Cbz Et Me
    178 cHex Cbz Et Et
    179 cHex Cbz Pr Me
    180 cHex Cbz Pr Et
    181 cHex Moc Me Me
    182 cHex Moc Me Et
    183 cHex Moc Et Me
    184 cHex Moc Et Et
    185 cHex Moc Pr Me
    186 cHex Moc Pr Et
    187 cHex Eoc Me Me
    188 cHex Eoc Me Et
    189 cHex Eoc Et Me
    190 cHex Eoc- Et Et
    191 cHex Eoc Pr Me
    192 cHex Eoc Pr Et
    193 cHex Ac Me Me
    194 cHex Ac Me Et
    195 cHex Ac Et Me
    196 cHex Ac Et Et
    197 cHex Ac Pr Me
    198 cHex Ac Pr Et
    199 cHex PhOCO Me Me
    200 cHex PhOCO Me Et
    201 cHex PhOCO Et Me
    202 cHex PhOCO Et Et
    203 cHex PhOCO Pr Me
    204 cHex PhOCO Pr Et
    205 cHex Bzl Me Me
    206 cHex Bzl Me Et
    207 cHex Bzl Et Me
    208 cHex Bzl Et Et
    209 cHex Bzl Pr Me
    210 cHex Bzl Pr Et
  • Among the above compounds, preferred compounds are the compounds of Exemplification Compound Nos. 1-2, 7-8, 13-14, 19-20, 25-26, 31-32, 37-38, 43-44, 49-50, 55-56, 61-62, 67-68, 73-74, 79-80, 85-86, 91-92, 97-98, 103-104, 109-110, 115-116, 121-122, 127-128, 133-134, 139-140, 145-146, 151-152, 157-158, 163-164, 169-170, 175-176, 181-182, 187-188, 193-194, 199-200, 205-206.
  • More preferred compounds are the compounds of Exemplification Compound Nos.1,7,13,19,25,31,37,43,49,55,61,67,73,79,85,91,97,103,109, 115,121,127,133,139,145,151,157,163,169,175,181,187,193,199,205.
  • Even more preferred compounds are the compounds of Exemplification compound number 43:
    • 2-t-butyl-4-methyl-1,3-oxazolidine-3,4-dicarboxylic acid 3-t-butyl ester 4-methyl ester Exemplification compound number 49:
    • 2-t-butyl-4-methyl-1,3-oxazolidine-3,4-dicarboxylic acid 3-benzyl ester 4-methyl ester Exemplification compound number 55:
    • 2-t-butyl-4-methyl-1,3-oxazolidine-3,4-dicarboxylic acid dimethyl ester Exemplification compound number 61:
    • 2-t-butyl-4-methyl-1,3-oxazolidine-3,4-dicarboxylic acid 3-ethyl ester 4-methyl ester Exemplification compound number 67:
    • 3-acetyl-2-t-butyl-4-methyl-1,3-oxozolidine-4-carboxylic acid methyl ester Exemplification compound number 73:
    • 2-t-butyl-4-methyl-1,3-oxazolidine-3,4-dicarboxylic acid 3-phenyl ester 4-methyl ester Exemplification compound number 79:
    • 3-benzoyl-2-t-butyl-4-methyl-1,3-oxazolidine-4-carboxylic acid methyl ester.
    (Table 2)
    Figure imgb0028
    Compound No. R2 R3 R4
    1 iPr Boc Me
    2 iPr Boc Et
    3 iPr Boc Pr
    4 iPr Cbz Me
    5 iPr Cbz Et
    6 iPr Cbz Pr
    7 iPr Moc Me
    8 iPr Moc Et
    9 iPr Moc Pr
    10 iPr Eoc Me
    11 iPr Eoc Et
    12 iPr Eoc Pr
    13 iPr Ac Me
    14 iPr Ac Et
    15 iPr Ac Pr
    16 iPr PhOCO Me
    17 iPr PhOCO Et
    18 iPr PhOCO Pr
    19 iPr Bzl Me
    20 iPr Bzl Et
    21 iPr Bzl Pr
    22 tBu Boc Me
    23 tBu Boc Et
    24 tBu Boc Pr
    25 tBu Cbz Me
    26 tBu Cbz Et
    27 tBu Cbz Pr
    28 tBu Moc Me
    29 tBu Moc Et
    30 tBu Moc Pr
    31 tBu Eoc Me
    32 tBu Eoc Et
    33 tBu Eoc Pr
    34 tBu Ac Me
    35 tBu Ac Et
    36 tBu Ac Pr
    37 tBu PhOCO Me
    38 tBu PhOCO Et
    39 tBu PhOCO Pr
    40 tBu Bzl Me
    41 tBu Bzl Et
    42 tBu Bzl Pr
    43 Et2CH Boc Me
    44 Et2CH Boc Et
    45 Et2CH Boc Pr
    46 Et2CH Cbz Me
    47 Et2CH Cbz Et
    48 Et2CH Cbz Pr
    49 Et2CH Moc Me
    50 Et2CH Moc Et
    51 Et2CH Moc Pr
    52 Et2CH Eoc Me
    53 Et2CH Eoc Et
    54 Et2CH Eoc Pr
    55 Et2CH Ac Me
    56 Et2CH Ac Et
    57 Et2CH Ac Pr
    58 Et2CH PhOCO Me
    59 Et2CH PhOCO Et
    60 Et2CH PhOCO Pr
    61 Et2CH Bzl Me
    62 Et2CH Bzl Et
    63 Et2CH Bzl Pr
    64 Ph Boc Me
    65 Ph Boc Et
    66 Ph Boc Pr
    67 Ph Cbz Me
    68 Ph Cbz Et
    69 Ph Cbz Pr
    70 Ph Moc Me
    71 Ph Moc Et
    72 Ph Moc Pr
    73 Ph Eoc Me
    74 Ph Eoc Et
    75 Ph Eoc Pr
    76 Ph Ac Me
    77 Ph Ac Et
    78 Ph Ac Pr
    79 Ph PhOCO Me
    80 Ph PhOCO Et
    81 Ph PhOCO Pr
    82 Ph Bzl Me
    83 Ph Bzl Et
    84 Ph Bzl Pr
    85 cHex Boc Me
    86 cHex Boc Et
    87 cHex Boc Pr
    88 cHex Cbz Me
    89 cHex Cbz Et
    90 cHex Cbz Pr
    91 cHex Moc Me
    92 cHex Moc Et
    93 cHex Moc Pr
    94 cHex Eoc Me
    95 cHex Eoc Et
    96 cHex Eoc Pr
    97 cHex Ac Me
    98 cHex Ac Et
    99 cHex Ac Pr
    100 cHex PhOCO Me
    101 cHex PhOCO Et
    102 cHex PhOCO Pr
    103 cHex Bzl Me
    104 cHex Bzl Et
    105 cHex Bzl Pr
  • Among the above compounds, preferred compounds are the compounds of Exemplification Compound Nos. 1, 4, 7,10, 13, 16, 19,22,25,28,31,34,37,40, 43, 46, 49, 52, 55, 58, 61, 64, 67, 70, 73, 76, 79, 82, 85, 88, 91, 94, 97, 100, and 103.
  • More preferred compounds are the compounds of Exemplification Compound Nos. 1, 4, 7, 10, 13, 16, 19, 22, 25, 28, 31, 34, 37, 40, 43, 46, 49, 52, 55, 58, and 61.
  • Even more preferred compounds as the compound of (Ib) of the present invention are the compounds of Exemplification compound number 22:
    • 2-t-butyl-4-hydroxymethyl-4-methyl-1,3-oxazolidine-3-carboxylic acid t-butyl ester, Exemplification compound number 25:
    • 2-t-butyl-4-hydroxymethyl-4-methyl-1,3-oxazolidine-3-carboxylic acid benzyl ester, Exemplification compound number 28:
    • 2-t-butyl-4-hydroxymethyl-4-methyl-1,3-oxazolidine-3-carboxylic acid methyl ester, Exemplification compound number 31:
    • 2-t-butyl-4-hydroxymethyl-4-methyl-1,3-oxazolidine-3-carboxylic acid ethyl ester, Exemplification compound number 34:
    • (3-acetyl-2-t-butyl-4-methyl-l,3-oxazolidin-4-yl)methanol, Exemplification compound number 37:
    • 2-t-butyl-4-hydroxymethyl-4-methyl-1,3-oxazolidine-3-carboxylic acid phenyl ester, Exemplification compound number 40:
    • (3-benzoyl-2-t-butyl-4-methyl-1, 3-oxazolidin-4-yl)methanol,
    as the compound of (Ic) of the present invention are the compounds of Exemplification compound number 22:
    • 2-t-butyl-4-formyl-4-methyl-1,3-oxazolidine-3-carboxylic acid t-butyl ester, Exemplification compound number 25:
    • 2-t-butyl-4-formyl-4-methyl-1,3-oxazolidine-3-carboxylic acid benzyl ester, Exemplification compound number 28:
    • 2-t-butyl-4-formyl-4-methyl-1,3-oxazolidine-3-carboxylic acid methyl ester, Exemplification compound number 31:
    • 2-t-butyl-4-formyl-4-methyl-1,3-oxazolidine-3-carboxylic acid ethyl ester, Exemplification compound number 34:
    • 3-acetyl-2-t-butyl-4-methyl-1, 3-oxazolidine-4-carboaldehyde, Exemplification compound number 37:
    • 2-t-butyl-4-formyl-4-methyl-1,3-oxazolidine-3-carboxylic acid phenyl ester, and Exemplification compound number 40:
    • 3-benzoyl-2-t-butyl-4-methyl-1,3-oxazolidine-4-carboaldehyde.
    (Table 3)
    Figure imgb0029
    Compound No. R2 R3 R4 X Y
    1 iPr Boc Me MeN H
    2 iPr Boc Me MeN Cl
    3 iPr Boc Me MeN Br
    4 iPr Boc Me MeN Oct
    5 iPr Boc Me MeN HepO
    6 iPr Boc Me MeN HepCO
    7 iPr Boc Me CHCH Cl
    8 iPr Boc Me CHCH Br
    9 iPr Boc Me CHCH I
    10 iPr Boc Me CHCH Oct
    11 iPr Boc Me CHCH HepO
    12 iPr Boc Me CHCH HepCO
    13 iPr Boc Et MeN H
    14 iPr Boc Et MeN Cl
    15 iPr Boc Et MeN Br
    16 iPr Boc Et MeN Oct
    17 iPr Boc Et MeN HepO
    18 iPr Boc Et MeN HepCO
    19 iPr Boc Et CHCH Cl
    20 iPr Boc Et CHCH Br
    21 iPr Boc Et CHCH I
    22 iPr Boc Et CHCH Oct
    23 iPr Boc Et CHCH HepO
    24 iPr Boc Et CHCH HepCO
    25 iPr Moc Me MeN H
    26 iPr Moc Me MeN Cl
    27 iPr Moc Me MeN Br
    28 iPr Moc Me MeN Oct
    29 iPr Moc Me MeN HepO
    30 iPr Moc Me MeN HepCO
    31 iPr Moc Me CHCH Cl
    32 iPr Moc Me CHCH Br
    33 iPr Moc Me CHCH I
    34 iPr Moc Me CHCH Oct
    35 iPr Moc Me CHCH HepO
    36 iPr Moc Me CHCH HepCO
    37 iPr Moc Et MeN H
    38 iPr Moc Et MeN Cl
    39 iPr Moc Et MeN Br
    40 iPr Moc Et MeN Oct
    41 iPr Moc Et MeN HepO
    42 iPr Moc Et MeN HepCO
    43 iPr Moc Et CHCH Cl
    44 iPr Moc Et CHCH Br
    45 iPr Moc Et CHCH I
    46 iPr Moc Et CHCH Oct
    47 iPr Moc Et CHCH HepO
    48 iPr Moc Et CHCH HepCO
    49 iPr PhOCO Me MeN H
    50 iPr PhOCO Me MeN Cl
    51 iPr PhOCO Me MeN Br
    52 iPr PhOCO Me MeN Oct
    53 iPr PhOCO Me MeN HepO
    54 iPr PhOCO Me MeN HepCO
    55 iPr PhOCO Me CHCH Cl
    56 iPr PhOCO Me CHCH Br
    57 iPr PhOCO Me CHCH I
    58 iPr PhOCO Me CHCH Oct
    59 iPr PhOCO Me CHCH HepO
    60 iPr PhOCO Me CHCH HepCO
    61 iPr PhOCO Et MeN H
    62 iPr PhOCO Et MeN Cl
    63 iPr PhOCO Et MeN Br
    64 iPr PhOCO Et MeN Oct
    65 iPr PhOCO Et MeN HepO
    66 iPr PhOCO Et MeN HepCO
    67 iPr PhOCO Et CHCH Cl
    68 iPr PhOCO Et CHCH Br
    69 iPr PhOCO Et CHCH I
    70 iPr PhOCO Et CHCH Oct
    71 iPr PhOCO Et CHCH HepO
    72 iPr PhOCO Et CHCH HepCO
    73 tBu Boc Me MeN H
    74 tBu Boc Me MeN Cl
    75 tBu Boc Me MeN Br
    76 tBu Boc Me MeN Oct
    77 tBu Boc Me MeN HepO
    78 tBu Boc Me MeN HepCO
    79 tBu Boc Me CHCH Cl
    80 tBu Boc Me CHCH Br
    81 tBu Boc Me CHCH I
    82 tBu Boc Me CHCH Oct
    83 tBu Boc Me CHCH HepO
    84 tBu Boc Me CHCH HepCO
    85 tBu Boc Et MeN H
    86 tBu Boc Et MeN Cl
    87 tBu Boc Et MeN Br
    88 tBu Boc Et MeN Oct
    89 tBu Boc Et MeN HepO
    90 tBu Boc Et MeN HepCO
    91 tBu Boc Et CHCH Cl
    92 tBu Boc Et CHCH Br
    93 tBu Boc Et CHCH I
    94 tBu Boc Et CHCH Oct
    95 tBu Boc Et CHCH HepO
    96 tBu Boc Et CHCH HepCO
    97 tBu Cbz Me MeN H
    98 tBu Cbz Me MeN Cl
    99 tBu Cbz Me MeN Br
    100 tBu Cbz Me MeN Oct
    101 tBu Cbz Me MeN HepO
    102 tBu Cbz Me MeN HepCO
    103 tBu Cbz Me CHCH Cl
    104 tBu Cbz Me CHCH Br
    105 tBu Cbz Me CHCH I
    106 tBu Cbz Me CHCH Oct
    107 tBu Cbz Me CHCH HepO
    108 tBu Cbz Me CHCH HepCO
    109 tBu Cbz Et MeN H
    110 tBu Cbz Et MeN Cl
    111 tBu Cbz Et MeN Br
    112 tBu Cbz Et MeN Oct
    113 tBu Cbz Et MeN HepO
    114 tBu Cbz Et MeN HepCO
    115 tBu Cbz Et CHCH Cl
    116 tBu Cbz Et CHCH Br
    117 tBu Cbz Et CHCH I
    118 tBu Cbz Et CHCH Oct
    119 tBu Cbz Et CHCH HepO
    120 tBu Cbz Et CHCH HepCO
    121 tBu Moc Me MeN H
    122 tBu Moc Me MeN Cl
    123 tBu Moc Me MeN Br
    124 tBu Moc Me MeN Oct
    125 tBu Moc Me MeN HepO
    126 tBu Moc Me MeN HepCO
    127 tBu Moc Me CHCH Cl
    128 tBu Moc Me CHCH Br
    129 tBu Moc Me CHCH I
    130 tBu Moc Me CHCH Oct
    131 tBu Moc Me CHCH HepO
    132 tBu Moc Me CHCH HepCO
    133 tBu Moc Et MeN H
    134 tBu Moc Et MeN Cl
    135 tBu Moc Et MeN Br
    136 tBu Moc Et MeN Oct
    137 tBu Moc Et MeN HepO
    138 tBu Moc Et MeN HepCO
    139 tBu Moc Et CHCH Cl
    140 tBu Moc Et CHCH Br
    141 tBu Moc Et CHCH I
    142 tBu Moc Et CHCH Oct
    143 tBu Moc Et CHCH HepO
    144 tBu Moc Et CHCH HepCO
    145 tBu Eoc Me MeN H
    146 tBu Eoc Me MeN Cl
    147 tBu Eoc Me MeN Br
    148 tBu Eoc Me MeN Oct
    149 tBu Eoc Me MeN HepO
    150 tBu Eoc Me MeN HepCO
    151 tBu Eoc Me CHCH Cl
    152 tBu Eoc Me CHCH Br
    153 tBu Eoc Me CHCH I
    154 tBu Eoc Me CHCH Oct
    155 tBu Eoc Me CHCH HepO
    156 tBu Eoc Me CHCH HepCO
    157 tBu Eoc Et MeN H
    158 tBu Eoc Et MeN Cl
    159 tBu Eoc Et MeN Br
    160 tBu Eoc Et MeN Oct
    161 tBu Eoc Et MeN HepO
    162 tBu Eoc Et MeN HepCO
    163 tBu Eoc Et CHCH Cl
    164 tBu Eoc Et CHCH Br
    165 tBu Eoc Et CHCH I
    166 tBu Eoc Et CHCH Oct
    167 tBu Eoc Et CHCH HepO
    168 tBu Eoc Et CHCH HepCO
    169 tBu PhOCO Me MeN H
    170 tBu PhOCO Me MeN Cl
    171 tBu PhOCO Me MeN Br
    172 tBu PhOCO Me MeN Oct
    173 tBu PhOCO Me MeN HepO
    174 tBu PhOCO Me MeN HepCO
    175 tBu PhOCO Me CHCH Cl
    176 tBu PhOCO Me CHCH Br
    177 tBu PhOCO Me CHCH I
    178 tBu PhOCO Me CHCH Oct
    179 tBu PhOCO Me CHCH HepO
    180 tBu PhOCO Me CHCH HepCO
    181 tBu PhOCO Et MeN H
    182 tBu PhOCO Et MeN Cl
    183 tBu PhOCO Et MeN Br
    184 tBu PhOCO Et MeN Oct
    185 tBu PhOCO Et MeN HepO
    186 tBu PhOCO Et MeN HepCO
    187 tBu PhOCO Et CHCH Cl
    188 tBu PhOCO Et CHCH Br
    189 tBu PhOCO Et CHCH I
    190 tBu PhOCO Et CHCH Oct
    191 tBu PhOCO Et CHCH HepO
    192 tBu PhOCO Et CHCH HepCO
    193 tBu Ac Me MeN H
    194 tBu Ac Me MeN Cl
    195 tBu Ac Me MeN Br
    196 tBu Ac Me MeN Oct
    197 tBu Ac Me MeN HepO
    198 tBu Ac Me MeN HepCO
    199 tBu Ac Me CHCH Cl
    200 tBu Ac Me CHCH Br
    201 tBu Ac Me CHCH I
    202 tBu Ac Me CHCH Oct
    203 tBu Ac Me CHCH HepO
    204 tBu Ac Me CHCH HepCO
    205 tBu Ac Et MeN H
    206 tBu Ac Et MeN Cl
    207 tBu Ac Et MeN Br
    208 tBu Ac Et MeN Oct
    209 tBu Ac Et MeN HepO
    210 tBu Ac Et MeN HepCO
    211 tBu Ac Et CHCH Cl
    212 tBu Ac Et CHCH Br
    213 tBu Ac Et CHCH I
    214 tBu Ac Et CHCH Oct
    215 tBu Ac Et CHCH HepO
    216 tBu Ac Et CHCH HepCO
    217 tBu Bzl Me MeN H
    218 tBu Bzl Me MeN Cl
    219 tBu Bzl Me MeN Br
    220 tBu Bzl Me MeN Oct
    221 tBu Bzl Me MeN HepO
    222 tBu Bzl Me MeN HepCO
    223 tBu Bzl Me CHCH Cl
    224 tBu Bzl Me CHCH Br
    225 tBu Bzl Me CHCH I
    226 tBu Bzl Me CHCH Oct
    227 tBu Bzl Me CHCH HepO
    228 tBu Bzl Me CHCH HepCO
    229 tBu Bzl Et MeN H
    230 tBu Bzl Et MeN Cl
    231 tBu Bzl Et MeN Br
    232 tBu Bzl Et MeN Oct
    233 tBu Bzl Et MeN HepO
    234 tBu Bzl Et MeN HepCO
    235 tBu Bzl Et CHCH Cl
    236 tBu Bzl Et CHCH Br
    237 tBu Bzl Et CHCH I
    238 tBu Bzl Et CHCH Oct
    239 tBu Bzl Et CHCH HepO
    240 tBu Bzl Et CHCH HepCO
    241 Et2CH Boc Me MeN H
    242 Et2CH Boc Me MeN Cl
    243 Et2CH Boc Me MeN Br
    244 Et2CH Boc Me MeN Oct
    245 Et2CH Boc Me MeN HepO
    246 Et2CH Boc Me MeN HepCO
    247 Et2CH Boc Me CHCH Cl
    248 Et2CH Boc Me CHCH Br
    249 Et2CH Boc Me CHCH I
    250 Et2CH Boc Me CHCH Oct
    251 Et2CH Boc Me CHCH HepO
    252 Et2CH Boc Me CHCH HepCO
    253 Et2CH Boc Et MeN H
    254 Et2CH Boc Et MeN Cl
    255 Et2CH Boc Et MeN Br
    256 Et2CH Boc Et MeN Oct
    257 Et2CH Boc Et MeN HepO
    258 Et2CH Boc Et MeN HepCO
    259 Et2CH Boc Et CHCH Cl
    260 Et2CH Boc Et CHCH Br
    261 Et2CH Boc Et CHCH I
    262 Et2CH Boc Et CHCH Oct
    263 Et2CH Boc Et CHCH HepO
    264 Et2CH Boc Et CHCH HepCO
    265 Et2CH Moc Me MeN H
    266 Et2CH Moc Me MeN Cl
    267 Et2CH Moc Me MeN Br
    268 Et2CH Moc Me MeN Oct
    269 Et2CH Moc Me MeN HepO
    270 Et2CH Moc Me MeN HepCO
    271 Et2CH Moc Me CHCH Cl
    272 Et2CH Moc Me CHCH Br
    273 Et2CH Moc Me CHCH I
    274 Et2CH Moc Me CHCH Oct
    275 Et2CH Moc Me CHCH HepO
    276 Et2CH Moc Me CHCH HepCO
    277 Et2CH Moc Et MeN H
    278 Et2CH Moc Et MeN Cl
    279 Et2CH Moc Et MeN B
    280 Et2CH Moc Et MeN Oct
    281 Et2CH Moc Et MeN HepO
    282 Et2CH Moc Et MeN HepCO
    283 Et2CH Moc Et CHCH Cl
    284 Et2CH Moc Et CHCH Br
    285 Et2CH Moc Et CHCH I
    286 Et2CH Moc Et CHCH Oct
    287 Et2CH Moc Et CHCH HepO
    288 Et2CH Moc Et CHCH HepCO
    289 Et2CH PhOCO Me MeN H
    290 Et2CH PhOCO Me MeN Cl
    291 Et2CH PhOCO Me MeN Br
    292 Et2CH PhOCO Me MeN Oct
    293 Et2CH PhOCO Me MeN HepO
    294 Et2CH PhOCO Me MeN HepCO
    295 Et2CH PhOCO Me CHCH Cl
    296 Et2CH PhOCO Me CHCH Br
    297 Et2CH PhOCO Me CHCH I
    298 Et2CH PhOCO Me CHCH Oct
    299 Et2CH PhOCO Me CHCH HepO
    300 Et2CH PhOCO Me CHCH HepCO
    301 Et2CH PhOCO Et MeN H
    302 Et2CH PhOCO Et MeN Cl
    303 Et2CH PhOCO Et MeN Br
    304 Et2CH PhOCO Et MeN Oct
    305 Et2CH PhOCO Et MeN HepO
    306 Et2CH PhOCO Et MeN HepCO
    307 Et2CH PhOCO Et CHCH Cl
    308 Et2CH PhOCO Et CHCH Br
    309 Et2CH PhOCO Et CHCH I
    310 Et2CH PhOCO Et CHCH Oct
    311 Et2CH PhOCO Et CHCH HepO
    312 Et2CH PhOCO Et CHCH HepCO
    313 Ph Boc Me MeN H
    314 Ph Boc Me MeN C1
    315 Ph Boc Me MeN Br
    316 Ph Boc Me MeN Oct
    317 Ph Boc Me MeN HepO
    318 Ph Boc Me MeN HepCO
    319 Ph Boc Me CHCH Cl
    320 Ph Boc Me CHCH Br
    321 Ph Boc Me CHCH I
    322 Ph Boc Me CHCH Oct
    323 Ph Boc Me CHCH HepO
    324 Ph Boc Me CHCH HepCO
    325 Ph Boc Et MeN H
    326 Ph Boc Et MeN Cl
    327 Ph Boc Et MeN Br
    328 Ph Boc Et MeN Oct
    329 Ph Boc Et MeN HepO
    330 Ph Boc Et MeN HepCO
    331 Ph Boc Et CHCH Cl
    332 Ph Boc Et CHCH Br
    333 Ph Boc Et CHCH I
    334 Ph Boc Et CHCH Oct
    335 Ph Boc Et CHCH HepO
    336 Ph Boc Et CHCH HepCO
    337 Ph Moc Me MeN H
    338 Ph _Moc Me MeN Cl
    339 Ph Moc Me MeN Br
    340 Ph Moc Me MeN Oct
    341 Ph Moc Me MeN HepO
    342 Ph Moc Me MeN HepCO
    343 Ph Moc Me CHCH Cl
    344 Ph Moc Me CHCH Br
    345 Ph Moc Me CHCH I
    346 Ph Moc Me CHCH Oct
    347 Ph Moc Me CHCH HepO
    348 Ph Moc Me CHCH HepCO
    349 Ph Moc Et MeN H
    350 Ph Moc Et MeN Cl
    351 Ph Moc Et MeN Br
    352 Ph Moc Et MeN Oct
    353 Ph Moc Et MeN HepO
    354 Ph Moc . Et MeN HepCO
    355 Ph Moc Et CHCH Cl
    356 Ph Moc Et CHCH Br
    357 Ph Moc Et CHCH I
    358 Ph Moc Et CHCH Oct
    359 Ph Moc Et CHCH HepO
    360 Ph Moc Et CHCH HepCO
    361 Ph PhOCO Me MeN H
    362 Ph PhOCO Me MeN Cl
    363 Ph PhOCO Me MeN Br
    364 Ph PhOCO Me MeN Oct
    365 Ph PhOCO Me MeN HepO
    366 Ph PhOCO Me MeN HepCO
    367 Ph PhOCO Me CHCH Cl
    368 Ph PhOCO Me CHCH Br
    369 Ph PhOCO Me CHCH I
    370 Ph PhOCO Me CHCH Oct
    371 Ph PhOCO Me CHCH HepO
    372 Ph PhOCO Me CHCH HepCO
    373 Ph PhOCO Et MeN H
    374 Ph PhOCO Et MeN Cl
    375 Ph PhOCO Et MeN Br
    376 Ph PhOCO Et MeN Oct
    377 Ph PhOCO Et MeN HepO
    378 Ph PhOCO Et MeN HepCO
    379 Ph PhOCO Et CHCH Cl
    380 Ph PhOCO Et CHCH Br
    381 Ph PhOCO Et CHCH I
    382 Ph PhOCO Et CHCH Oct
    383 Ph PhOCO Et CHCH HepO
    384 Ph PhOCO Et CHCH HepCO
  • Among the above compounds, preferred compounds are the compounds of Exemplification Compound Nos.:
    • 1-6, 25-30, 49-54, 73-78, 97-102, 121-126, 145-150, 169-174,193-198, 217-222, 241-246, 265-270, 289-294, 313-318, 337-342, and 361-366.
  • More preferred compounds are the compounds of Exemplification Compound Nos.:
    • 1-3, 25-27, 49-51, 73-75, 97-99, 121-123, 145-147, 169-171, 193-195, 217-219, 241-243, 265-267, 289-291, 313-315, 337-339, and 361-363.
  • Even more preferred compounds are the compounds of
    • Exemplification compound number 73:
      • 2-t-butyl-4-methyl-4-[2-(1-methyl-1 H-pyrrol-2-yl)ethyl]-1,3-oxazolidine-3-carboxylic acid t-butyl ester,
    • Exemplification compound number 97:
      • 2-t-butyl-4-methyl-4-[2-(1-methyl-1H-pyrrol-2-yl)ethyl]-1,3-oxazolidine-3-carboxylic acid benzyl ester,
    • Exemplification compound number 121:
      • 2-t-butyl-4-methyl-4-[2-(1-methyl-1H-pyrrol-2-yl)ethyl]-1,3-oxazolidine-3-carboxylic acid methyl ester,
    • Exemplification compound number 145:
      • 2-t-butyl-4-methyl-4-[2-(1-methyl-1H-pyrrol-2-yl)ethyl]-1,3-oxazolidine-3-carboxylic acid ethyl ester,
    • Exemplification compound number 169:
      • 2-t-butyl-4-methyl-4-[2-(1-methyl-1 H-pyrrol-2-yl)ethyl]-1,3-oxazolidine-3-carboxylic acid phenyl ester,
    • Exemplification compound number 193:
      • 3-acetyl-2-t-butyl-4-methyl-4-[2-(1-methyl-1H-pyrrol-2-yl)ethyl]-1,3-oxozalidine, and
    • Exemplification compound number 217:
      • 3-benzoyl-2-t-butyl-4-methyl-4-[2-(1-methyl-1H-pyrrol-2-yl)ethyl]-1,3-oxazolidine.
    [Advantage of the invention]
  • The present invention is useful for providing the optically active 4,4-di-substituted oxazolidine derivatives and procedures for their preparation. The preparation procedures of the present invention have excellent advantages in the following respects, compared with the prior art: 1) increase in yield, 2) improvement in stereoselectivity, 3) extremely low-temperature reaction which is unsuitable for industrial large-scale synthesis is not necessary, and 4) column-chromatographic purification of intermediates is not needed in any step of these synthetic processes.
  • Furthermore, the compounds having the general formula (Id), which are the optically active 4,4-di-substituted oxazolidine derivatives encompassed in the present invention, are useful as synthetic intermediates in the preparation of optically active α,α-di-substituted α-amino acid derivatives having an excellent glutamate receptor antagonistic action or optically active α,α-di-substituted α-amino alcohol derivatives having new immunosuppressive action.
  • As shown in the following reaction scheme, for example, the compound (VII) described in non-patent literatures 8 and 9 mentioned hereinbefore, an immunosuppressive agent having a new mode action, can be synthesized from the compounds of the general formula (Id) of the present invention [wherein, R2 and R3 have the same meanings as those indicated hereinbefore, R4 represents a methyl group, X represent a vinylene group, and Y represents a heptyloxy group] by removing R2 and R3 groups, both of which are protecting groups, by treatment with an acid, a base or the like according to conventional procedures.
    Figure imgb0030
  • Furthermore, according to the present invention, the substituted methylenephosphonium salt which is useful as a synthetic intermediate in the preparation of the compounds having the general formula (Id) and various kinds of medicines can be obtained conveniently in a high yield.
  • The substituted methylenephosphonium salt having the general formula (IV'-b) or (IV'-c) prepared by the present invention is, for example, as shown in the following reaction scheme, useful as the intermediate in the preparation of immunosuppressive agents having the general formula (VI'-b) or (VI'-c) disclosed in W003/059880 .
    Figure imgb0031
     [In the above reaction scheme, Y represents an ethylene group, a vinylene group, an ethynylene group, a group of formula -E-CH2- (wherein, E represents a carbonyl group, a group of formula -CH(OH)-, an oxygen atom, a sulfur atom or a group of formula - NH-), Z represents a single bond, a C1-C10 alkylene group or a C1-C10 alkylene group which has an oxygen atom or a sulfur atom in or at an end of the carbon chain, and R5 represents a hydrogen atom, a cycloalkyl group, an aryl group or a heterocyclic group]
  • Additionally, as shown in following reaction scheme, the substituted methylenephosphonium salt having the general formula (IV'-d) prepared by the present invention is useful since the synthetic intermediate (VI-d) in the preparation of the compound having the general formula (VI'-d) disclosed in WO94/08943 , which is used as an immunosuppressive agent, can be prepared by reacting this invented compound (IV'-d) with a compound having a formula (D) described in Bioorganic and Medicinal Chemistry, 11 (2003) 2529-2539.
    Figure imgb0032
     [in above reaction scheme, Rc represents a C1-C10 alkyl group or the like, and X represents a halogen atom]
    • [Best mode for carrying out the invention]
  • The compounds of the present invention can be prepared according to the procedures described below.
  • The compounds employed in the invented procedures are generally known compounds and can be prepared from known compounds according to known procedures, but some of them are commercially available. As the known procedures described above, there are the procedures described, for example, in "Organic Functional Group Preparation", Second Edition, Academic Press, Inc., 1989, and "Comprehensive Organic Transformations", VCH Publishers Inc., 1989.
  • Depending on the reactivity of functional groups, it is necessary to protect these functional groups contained in the starting materials and/or intermediates generated in the reaction processes using suitable protecting groups, that can be removed to convert the protected functional group(s) into said functional group(s) easily, before initiation of the reaction or at the suitable steps. When the functional group(s) are protected by the suitable protecting group(s), the desired compound can be obtained by removing the protecting group(s), if necessary.
  • Such functional group is, for example, a hydroxyl group, a carboxyl group, a hydroxyl group, a carbonyl group and an amino group, and the protecting groups are found in Green and Wuts: "Protective Groups in Organic Synthesis", 3rd edition, John Willey and Sons, Inc., 1999, and a suitable protecting group for them can be used depending on the reaction conditions.
  • The protecting group employed for the carboxyl group is, for example, a C1-C6 alkyl (for example, a methyl, ethyl, propyl, isopropyl, butyl or t-butyl group), C7-C10 aralkyl (for example, a benzyl group), phenyl, trityl, silyl (for example, a trimethylsilyl, triethylsilyl, dimethylphenylsilyl, t-butyldimethylsilyl or t-butyldiethylsilyl group), or C2-C6 alkenyl group (for example, a 1-allyl group). These groups may optionally be substituted with from 1 to 3 halogen atoms (for example, a fluorine, chlorine, bromine or iodine atom), a C1-C6 alkoxyl group (for example, a methoxy, ethoxy or propoxy group), or a nitro group.
  • The protecting group employed for the hydroxyl group is, for example, a C1-C6 alkyl (for example, a methyl, ethyl, propyl, isopropyl, butyl or t-butyl group), phenyl, trityl, C7-C11 aralkyl (for example, a benzyl group), formyl, C1-C6 alkylcarbonyl (for example, an acetyl or propionyl group), benzoyl, C7-C11 aralkylcarbonyl (for example, a benzylcarbonyl group), 2-tetrahydropyranyl, 2-tetrahydrofuranyl, silyl (for example, a trimethylsilyl, triethylsilyl, dimethylphenylsilyl, t-butyldimethylsilyl or t-butyldiethylsilyl group) or C2-C6 alkenyl group (for example, a 1-allyl group). These groups may optionally be substituted with from 1 to 3 halogen atoms (for example, a fluorine, chlorine, bromine or iodine atom), a C1-C6 alkyl group (for example, a methyl, ethyl or n-propyl group), a C1-C6 alkoxyl group (for example, a methoxy, ethoxy or propoxy group) or a nitro group.
  • The protecting group employed for the carbonyl group is, for example, a cyclic acetal (for example, 1,3-dioxane) or non-cyclic acetal group (for example, di-C1-C6 alkyl acetal group).
  • The protecting group employed for the amino group is, for example, a formyl, C1-C6 alkylcarbonyl (for example, an acetyl or propionyl group), C1-C6 alkoxycarbonyl (for example, a methoxycarbonyl, ethoxycarbonyl or t-butoxycarbonyl group), benzoyl, C7-C11 aralkylcarbonyl (for example, a benzylcarbonyl group), C7-C14 aralkyloxycarbonyl (for example, a benzyloxycarbonyl or 9-fluorenylmethoxycarbonyl group), trityl, phthaloyl, N,N-dimethylaminomethylene, silyl (for example, a trimethylsilyl, triethylsilyl, dimethylphenylsilyl, t-butyldimethylsilyl or t-butyldiethylsilyl group) or C2-C6 alkenyl group (for example, a 1-allyl group). These groups may optionally be substituted with from 1 to 3 halogen atoms (for example, a fluorine, chlorine, bromine or iodine atom), a C1-C6 alkoxyl group (for example, a methoxy, ethoxy or propoxy group) or a nitro group.
  • The removal of the protecting groups described above is carried out by known procedures such as procedures using an acid, a base, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate or trialkylsilyl halide (for example, trimethylsilyl iodide or trimethylsilyl bromide) or a reduction procedure.
    • Method A
  • The method A is a process for the preparation of a compound having the general formula (Ia).
    Figure imgb0033
  • In the above reaction scheme, R, R2, R3 and R4 have the same meanings as those indicated hereinbefore.
  • The compound having the general formula (II) was synthesized according to the procedure described in the literature (Angew. Chem. GE 100, 10, 1988, 1398-1404). In Step A1, the compound having the general formula (VIII) can be prepared by the esterification of (S)-serine (VII), in Step A2, the compound having the general formula (IX) can be prepared by protecting the amino alcohol compound having the general formula (VIII) obtained above with a R2-acetal group, and in Step A3, a compound having the general formula (II) can be prepared by protecting the nitrogen atom of the compound having the general formula (IX) obtained above with R3.
  • Furthermore, in Step A4 which is a reaction of the present invention, a compound having the general formula (Ia) can be prepared stereoselectively by reacting a compound having the general formula (II) with an alkylating agent in the presence of a coordinating reagent and a base and in the presence of an inert solvent or absence of a solvent. This process is a modified process of the method by Dieter Seebach et al., and is improved to enable this invented procedure to be applied to industrial large-scale manufacturing.
  • In the method by Dieter Seebach et al., the compound having the general formula (Ia) is synthesized by adding a base first to the compound of the general formula (II) in which R is a methyl group, R2 is a t-butyl group and R3 is a formyl group (this compound is different from the invented compound in respect that R3 is a formyl group) and followed by addition of an alkylating agent to the resulting mixture, but the desired compound can be obtained only in the yield of about 40 to 70 %. In the present invention, however, it was discovered that the compound of the general formula (Ia) can be synthesized in a high yield by addition of each reagent under reaction conditions which are appropriate to the compound of general formula (II), for example, by the addition of an alkylating reagent and a coordinating reagent to the compound of general formula (II) first and followed by the addition of a base to the resulting mixture obtained. Furthermore, in the present invention, various reaction conditions are improved, and the present invention provides several advantages in respect that the extremely low-temperature reaction (about -78°C), which is an indispensable step in the conventional procedure and additionally unsuitable for the industrial large-scale manufacturing, can be avoided by selection of a suitable base and coordinating reagent, and a compound having the general formula (Ia) can be synthesized in a high yield even at an industrially applicable temperature, for example, at a temperature ranging from - 25°C to 10°C. In contrast to the prior art which is only the results of researches at the academic level, the present process of the present invention is superior to the prior art in respect that the invented procedure is on an industrially utilizable level.
  • The alkylating agent employed in the above reaction is not particularly restricted provided that it can be generally used in the alkylation of ester-enolates, and can be, for example, methyl chloride, methyl bromide, methyl iodide, methyl methanesusulfonate, methyl trifluoromethanesulfonate, methyl p-toluenesulfonate, dimethyl sulfate, ethyl chloride, ethyl bromide, ethyl iodide, ethyl methanesusulfonate, ethyl trifluoromethanesulfonate, ethyl p-toluenesulfonate, diethyl sulfate, propyl chloride, propyl bromide, propyl iodide, propyl methanesusulfonate, propyl trifluoromethanesulfonate, propyl p-toluenesulfonate or dipropyl sulfate, and is preferably methyl bromide, methyl iodide, ethyl bromide, ethyl iodide, propyl bromide or propyl iodide, and more preferably methyl bromide or methyl iodide.
  • The coordinating reagents employed in the above reactions can be, for example, a urea such as 1,3-diinethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU) or 1,3-dimethyl-2-imidazolidinone (DMI); an amide such as 1-methyl-2-pyrrolidinone (NMP), N,N-dimethylacetamide (DMAc) or N,N-dimethylformamide (DMF); a sulfoxide such as dimethyl sulfoxide (DMSO); a crown ether such as 12-crown-4, 15-crown-5 or 18-crown-6; or an ethylene glycol such as diethylene glycol dimethyl ether (diglyme), triethylene glycol dimethyl ether (triglyme), tetraethylene glycol dimethyl ether (tetraglyme) or polyethylene glycol, and is preferably DMPU, DMI, NMP, DMF, DMSO, triglyme or tetraglyme, and more preferably triglyme or tetraglyme.
  • The base employed in the above reaction is not particularly restricted provided that it is a low-nucleophilic base, and can be, for example, an alkali metal amide such as lithium bis(trimethylsilyl)amide (LHMDS), lithium diisopropylamide (LDA), sodium bis(trimethylsilyl)amide (SHMDS) or potassium bis(trimethylsilyl)amide (KHMDS); or an alkali-metal alkoxide such as sodium t-butoxide or potassium t-butoxide, and is preferably potassium t-butoxide.
  • The inert solvent employed in the above reaction is not particularly restricted provided that it has no adverse effect on the reaction, and can be, for example, an ether such as tetrahydrofuran, diethyl ether, t-butylmethyl ether, 1,4-dioxane or dimethoxyethane; an aromatic hydrocarbon such as toluene or xylene; an aliphatic hydrocarbon such as hexane or heptane; or a mixed solvent thereof, and is preferably an ether, and more preferably tetrahydrofuran or methoxyethane.
  • The reaction temperature employed in the above reaction is different depending on the starting material, the reagent used and the sort of solvent, but is generally between - 100°C and 30°C, preferably between -80°C and 10°C, and most preferably between - 25°C and 10°C.
  • The reaction time employed in the above reaction is different depending on the reaction temperature, the starting material, the reagent and the sort of solvent employed, but is generally from 5 minutes to 24 hours, and preferably from 30 minutes to 5 hours.
  • After the reaction is completed, the desired compound of this reaction can be isolated from the reaction mixture by conventional treatments. The desired compound can be isolated, for example, by neutralization of the reaction mixture, if necessary, or filtration of the reaction mixture when insoluble material is present in the reaction mixture, extraction of the neutralized solution or the filtrate with an organic solvent immiscible with water such as toluene, washing the resulting organic layer with water, separation of the organic layer containing the desired compound, and then evaporation of the organic solvent under reduced pressure.
  • The product thus obtained, if necessary, can be further isolated and purified by conventional treatments, for example, by recrystallization or reprecipitation, or by conventional procedures generally used in the isolation and purification of organic compounds (for example, absorption column chromatography using a carrier such as silica gel, alumina or Florisil consisting of magnesium and silica gel;partition column chromatography using Sephadex LH-20 (product of Pharmacia Co., Ltd.), Amberlite XAD-11 (product of Rohm & Hass Co., Ltd.) or Diaion HP-20 (product of Mitsubishi Chemicals Co., Ltd.); ion exchange chromatography; or normal phase or reversed phase column chromatography using silica gel or alkylated silica gel, and preferably by column chromatography using silica gel).
    • Method B
  • Step B1 is a process for the preparation of a compound having the general formula (Ib).
    Figure imgb0034
  • In the above reaction scheme, R, R2, R3 and R4 have the same meanings as those indicated hereinbefore.
  • A compound having the general formula (Ib) can be prepared by reacting a compound having the general formula (Ia) with a reducing agent in an inert solvent.
  • The reducing agent employed in the above reaction is not particularly restricted provided that it is generally used in the reduction of an ester to a primary alcohol, and can be, for example, a metal salt ofborohydride such as lithium borohydride, sodium borohydride or potassium borohydride; a metal salt of aluminum hydride such as lithium aluminum hydride, sodium aluminum hydride or sodium bis(2-methoxyethoxy)aluminum hydride; or a metal hydride such as isobutylaluminum hydride, and these reducing agents described above can be also used as a combination with a lithium halogenide such as lithium chloride, lithium bromide or lithium iodide, or a lanthanide halogenide such as cerium trichloride, samarium trichloride or europium trichloride, and is preferably lithium borohydride, sodium borohydride, potassium borohydride or sodium bis(2-methoxyethoxy)aluminum hydride, or a combination of these reducing agents and a lithium halogenide, more preferably a combination of sodium borohydride or potassium borohydride and a lithium halogenide, and still more preferably a combination of potassium borohydride and lithium chloride.
  • The inert solvent employed in the above reaction is different depending on the sort of reagents used, but is not particularly restricted provided that it has no adverse effect on the reaction, and can be, for example, an aliphatic hydrocarbon such as hexane or heptane; an aromatic hydrocarbon such as toluene or xylene; a halogenated hydrocarbon such as dichloromethane or 1,2-dichloroethane; an ether such as tetrahydrofuran, diethyl ether or t-butyl methyl ether; an alcohol such as methanol, ethanol or n-propanol; or a mixed solvent of these solvents, and is preferably an aromatic hydrocarbon, an ether or an alcohol, or a mixed solvent of these solvents, and more preferably tetrahydrofuran or toluene, or a mixed solvent of these solvents.
  • The reaction temperature employed in the above reaction is different depending on the starting material, the reagent used and the sort of solvent, but is generally between - 80°C and 120°C, and preferably between -20°C and 50°C.
  • The reaction time employed in the above reaction is different depending on the reaction temperature, the starting material, the reagent used and the sort of solvent employed, but is generally from 5 minutes to 48 hours, and preferably from 30 minutes to 10 hours.
  • After the reaction is completed, the desired compound of this reaction can be isolated from the reaction mixture and purified in the same manner as those described in the Method A.
    • Method C
  • Step C1 is a process for the preparation of a compound having the general formula (Ic).
    Figure imgb0035
  • In the above reaction scheme, R2, R3 and R4 have the same meanings as those indicated hereinbefore.
  • A compound having the general formula (Ic) can be prepared by reacting a compound having the general formula (Ib) with an oxidizing agent in an inert solvent.
  • The oxidizing agent employed in the above reaction is not particularly restricted provided that it is generally used in the oxidation of a primary alcohol to a corresponding aldehyde, and can be, for example, a chromic acid compound such as potassium chromate, chromic acid-sulfuric acid complex or chromic acid-pyridine complex; a combination of a co-oxidizing agent such as a salt of hypochlorous acid, a salt of bromous acid, N-chlorosuccinimide or molecular oxygen and a catalytic amount of 2,2,6,6-tetramethylpiperidinooxy, free radical (TEMPO) and another salt; a reagent used for DMSO oxidation (complex of dimethylsufoxide and dicyclohexylcarbodiimide, oxalyl chloride, acetic anhydride or phosphorus pentoxide, or a complex of pyridine-sulfuric anhydride); a combination of a transition metal catalyst such as a copper complex or a ruthenium complex and molecular oxygen, or a transition metal catalyst and an organic oxidizing agent such as N-methylmorpholinoxide, and is preferably a combination of a co-oxidizing agent and TEMPO and another salt, more preferably a combination of sodium hypochlorite, TEMPO, sodium bromide and sodium hydrogencarbonate.
  • The inert solvent employed in the above reaction is different depending on the sort of reagents used, but is not particularly restricted provided that it has no adverse effect on the reaction, and when the combination of a salt of hypochlorous acid, TEMPO and other salts is used as the oxidizing agent, the inert solvent employed can be an aliphatic hydrocarbon such as hexane or heptane; an aromatic hydrocarbon such as toluene or xylene; a halogenated hydrocarbon such as dichloromethane or 1,2-dichloroethane; an ester such as ethyl acetate or butyl acetate; or a mixed solvent of the solvents described above and water, and is preferably a mixed solvent of toluene and water.
  • The reaction temperature employed in the above reaction is different depending on the starting material, the reagent used and the sort of solvent, but is generally between - 50°C and 100°C, and preferably between -10°C and 20°C.
  • The reaction time employed in the above reaction is different depending on the reaction temperature, the starting material, the reagent used and the sort of solvent employed, but is generally from 5 minutes to 48 hours, and preferably from 30 minutes to 5 hours.
  • After the reaction is completed, the desired compound of this reaction can be isolated from the reaction mixture and purified in the same manner as those described in the Method A.
    • Method D
  • Step D1 is an alternative procedure to Method C for the preparation of a compound having the general formula (Ic).
    Figure imgb0036
  • In the above reaction scheme, R, R2, R3 and R4 have the same meanings as those indicated hereinbefore.
  • In this step, a compound having the general formula (Ic) can be prepared in one step by reacting a compound having the general formula (Ia) with a reducing agent in an inert solvent without passing through a compound having the general formula (Ib).
  • The reducing agent employed in the above reaction is not particularly restricted provided that it is generally used in a reduction reaction of an ester into an aldehyde, and can be, for example, a metal salt of borohydride such as lithium borohydride, sodium borohydride or potassium borohydride; a metal salt of aluminum hydride such as lithium aluminum hydride, sodium aluminum hydride or sodium bis(2-methoxyethoxy)aluminum hydride; or a metal hydride such as isobutylaluminum hydride, and these reducing agents described above can be also used as a combination with an organic amine such as pyrrolidine or morpholine, and is preferably sodium bis(2-methoxyethoxy)aluminum hydride or a combination thereof with an organic amine, and more preferably sodium bis(2-methoxyethoxy)aluminum hydride.
  • The inert solvent employed in the above reaction is not particularly restricted provided that it has no adverse effect on the reaction, and can be, for example, an aliphatic hydrocarbon such as hexane or heptane; an aromatic hydrocarbon such as toluene or xylene; or a halogenated hydrocarbon such as dichloromethane or 1,2-dichloroethane, and is preferably toluene.
  • The reaction temperature employed in the above reaction is different depending on the starting material, the reagent used and the sort of solvent, but is generally between - 100°C and 50°C, and preferably between -50°C and 20°C.
  • The reaction time employed in the above reaction is different depending on the reaction temperature, the starting material, the reagent used and the sort of solvent employed, but is generally from 5 minutes to 48 hours, and preferably from 30 minutes to 10 hours.
  • After the reaction is completed, the desired compound of this reaction can be isolated from the reaction mixture and purified in the same manner as those described in the Method A.
    • Method E
  • The method E is a method for the preparation of compounds having the general formulae (Id') and (Id).
    Figure imgb0037
  • In the above reaction scheme, R, R2, R3, R4, W, X and Y have the same meanings as those indicated hereinbefore.
  • Step E1 is a process for the preparation of a compound having the general formula (Id') by reacting a compound having the general formula (Ic) with a compound having the general formula (IV) in the presence of a base in an inert solvent.
  • The base employed in the above reaction is not particularly restricted provided that it is generally used in the Wittig reaction, and can be, for example, an alkali metal carbonate such as sodium carbonate, potassium carbonate or cesium carbonate; an alkali metal hydride such as lithium hydride or sodium hydride; an alkali metal hydroxide such as sodium hydroxide, potassium hydroxide, barium hydroxide or lithium hydroxide; an alkali metal alkoxide such as sodium methoxide, sodium ethoxide, sodium tert-butoxide or potassium tert-butoxide; an organic base such as 1,8-diazabicyclo[5.4.0]undec-7-ene; an alkyllithium such as butyllithium or an alkylmagnesium halide such as butylmagnesium bromide; an alkali metal amide such as lithium diisopropylamide, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide or potassium bis(trimethylsilyl)amide, and is preferably an alkali metal carbonate, an alkali metal alkoxide or an alkali metal amide, and more preferably potassium carbonate, cesium carbonate, sodium methoxide, sodium ethoxide or potassium tert-butoxide.
  • The inert solvent employed in the above reaction is not particularly restricted provided that it has no adverse effect on the reaction, and can be, for example, an ether such as tetrahydrofuran, diethyl ether, t-butylmethyl ether; a urea such as 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone or 1,3-dimethyl-2-imidazolidinone; an amide such as 1-methyl-2-pyrrolidinone, N,N-dimethylacetamide or N,N-dimethylformamide; a sulfoxide such as dimethyl sulfoxide; or an alkylnitrile such as acetonitrile, and preferably a urea or an amide, and more preferably N,N-dimethylformamide.
  • The reaction temperature employed in the above reaction is different depending on the starting material, the reagent used and the sort of solvent, but is generally between - 80°C and 30°C, and preferably between -20°C and 10°C.
  • The reaction time employed in the above reaction is different depending on the reaction temperature, the starting material, the reagent used and the sort of solvent employed, but is generally from 5 minutes to 48 hours, and preferably from 30 minutes to 5 hours.
  • After the reaction is completed, the desired compound of this reaction can be isolated from the reaction mixture and purified in the same manner as those described in the Method A.
  • Step E2 is a process for the preparation of a compound having the general formula (Id) by reacting a compound having the general formula (Id') with a reducing agent in an inert solvent. The reduction reaction is preferably carried out with a metal catalyst in a hydrogen atmosphere.
  • The metal catalyst employed in the above reaction is not particularly restricted provided that it can generally be used for catalytic reduction, and can be, for example, a heterogeneous palladium-type catalyst such as palladium-charcoal, palladium-alumina or palladium-zeolite; a nickel-type catalyst such as Raney nickel; a platinum catalyst such as platinum oxide or platinum-charcoal; a rhodium-type catalyst such as rhodium-aluminum oxide, rhodium-charcoal or triphenylphosphine- rhodium chloride; or a noble metal catalyst other than the catalysts described above such as ruthenium-charcoal, and preferably a heterogeneous palladium-type catalyst such as palladium-charcoal, palladium-alumina or palladium-zeolite.
  • The pressure of hydrogen employed in the above reaction is generally between 0.1 and 50 atmospheric pressures, and preferably between 1 and 10 atmospheric pressures.
  • The inert solvent employed in the above reaction is not particularly restricted provided that it has no adverse effect on the reaction, and can be, for example, an aliphatic hydrocarbon such as hexane or heptane; an aromatic hydrocarbon such as toluene or xylene; a halogenated hydrocarbon such as dichloromethane or 1,2-dichloroethane; an ester such as ethyl acetate or butyl acetate; an ether such as tetrahydrofuran, diethyl ether or t-butyl methyl ether; an amide such as 1-methyl-2-pyrrolidinone, N,N-dimethylformamide or N,N-dimethylacetamide; an alcohol such as methanol, ethanol or n-propanol; an organic acid such as formic acid or acetic acid; an aqueous inorganic acid solution such as aqueous hydrochloric acid solution or aqueous sulfuric acid solution; or water; or a mixed solvent of water and solvent(s) described above, and preferably an alcohol, an ether, or a mixed solvent of these solvents and water, and more preferably methanol or ethanol.
  • The reaction temperature employed in the above reaction is different depending on the starting material, the reagent used and the sort of solvent, but is generally between - 20°C and 100°C, and preferably between 0°C and 50°C.
  • The reaction time employed in the above reaction is different depending on the reaction temperature, the starting material, the reagent used and the sort of solvent employed, but is generally from 5 minutes to 48 hours, and preferably from 30 minutes to 5 hours.
  • After the reaction is completed, the desired compound of this reaction can be isolated from the reaction mixture and purified in the same manner as those described in the Method A.
    • Method F
  • Method F is an alternative procedure to Method E for the preparation of a compound having the general formula (Id).
    Figure imgb0038
  • In the above reaction scheme, R, R2, R3, R4, W, X, Y and Z have the same meanings as those indicated hereinbefore.
  • Step F1 is a process for the preparation of a compound having the general formula (V') and achieved by reacting a compound having the general formula (Ib) with a halogenating agent or a sulfonylating agent in the presence or absence of a base in an inert solvent.
  • The halogenating agent employed in the above reaction is not particularly restricted provided that it is generally used for the halogenation of a primary alcohol, and can be, for example, oxalyl chloride; a thionyl halide such as thionyl chloride or thionyl bromide; a phosphorus trihalogenide such as phosphorus trichloride or phosphorus tribromide; a phosphorus pentahalide such as phosphorus pentachloride or phosphorus pentabromide; a phosphorus oxyhalide such as phosphorus oxychloride or phosphorus oxybromide; a Vilsmeier type reagent such N,N-dimethylchloroforminium chloride or N,N-dimethylbromoforminium bromide; a combination of a phosphine such as triphenylphosphine and a halogen atom or a tetrahalogenated methane; or a combination of a phosphine such as a combination of triphenylphosphine, diethyl azodicarboxylate and lithium bromide, an azodicarboxylic acid ester and a halogenated metal, and preferably a combination of triphenylphosphine and iodine.
  • The sulfonylating agent employed in the above reaction is not particularly restricted provided that it is generally used for sulfonylation reaction, and can be, for example, a sulfonyl halide such as methanesulfonyl chloride or p-toluenesulfonyl chloride, or a sulfonic anhydride, and is preferably methanesulfonyl chloride or p-toluenesulfonyl chloride.
  • The base employed in the above reaction is different depending on the sort of reagents used, but is not particularly restricted, and can be, for example, an organic base such as imidazole, pyridine, triethylamine or N-methylimidazole, and is preferably as imidazole, pyridine or triethylamine.
  • The inert solvent employed in the above reaction is different depending on the sort of reagents used, but is not particularly restricted provided that it has no adverse effect on the reaction, and can be, for example, an aliphatic hydrocarbon such as hexane or heptane; an aromatic hydrocarbon such as toluene or xylene; a halogenated hydrocarbon such as dichloromethane or 1,2-dichloroethane; an ester such as ethyl acetate or butyl acetate; an ether such as tetrahydrofuran, diethyl ether or t-butyl methyl ether; or an amide such as 1-methyl-2-pyrrolidinone, N,N-dimethylformamide or N,N-dimethylacetamide, and is preferably toluene.
  • The reaction temperature employed in the above reaction is different depending on the starting material, the reagent used and the sort of solvent, but is generally between - 20°C and 120°C, and preferably between 0°C and 80°C.
  • The reaction time employed in the above reaction is different depending on the reaction temperature, the starting material, the reagent used for the reaction and the sort of solvent employed, but is generally from 5 minutes to 48 hours, and preferably from 1 hour to 10 hours.
  • The compound having the general formula (V') in which Z is a halogen group can be prepared by reacting a compound having the general formula (V') in which Z is a sulfonyl group with a halogenating agent in an inert solvent.
  • The halogenating agent employed in the above reaction is not particularly restricted provided that it is generally used for halogenation of a compound in which a moiety of primary alcohol is sulfonylated, and can be, for example, a halogenated metal such as lithium chloride, lithium bromide, lithium bromide, sodium bromide, sodium iodide, potassium iodide, zinc chloride, zinc bromide or zinc iodide, and is preferably sodium iodide or potassium iodide.
  • The inert solvent employed in the above reaction is not particularly restricted provided that it has no adverse effect on the reaction, and can be, for example, an ether such as tetrahydrofuran, diethyl ether or t-butyl methyl ether; an amide such as 1-methyl-2-pyrrolidinone, N,N-dimethylformamide (DMF), or N,N-dimethylacetamide; an alcohol such as methanol, ethanol or n-propanol; or a sulfoxide such as dimethyl sulfoxide, and is preferably DMF.
  • The reaction temperature employed in the above reaction is different depending on the starting material, the reagent used and the sort of solvent, but is generally between - 20°C and 120°C, and preferably between 20°C and 100°C.
  • The reaction time employed in the above reaction is different depending on the reaction temperature, the starting material, the reagent used for the reaction and the sort of solvent employed, but is generally from 30 minutes to 48 hours, and preferably from 1 hour to 10 hours.
  • After the reaction is completed, the desired compound of this reaction can be isolated from the reaction mixture and purified in the same manner as those described in the Method A.
    • Step F2
  • Step F2 is a process for the preparation of a compound having the general formula (V).
  • This step is achieved by reacting a compound having the general formula (V') with a phosphine or a phosphonic acid ester in an inert solvent.
  • The phosphine employed in the above reaction is not particularly restricted provided that it is generally used for the synthesis of a phosphonium salt, and can be, for example, trimethylphosphine, triethylphosphine, tripropylphosphine, tributylphosphine or triphenylphosphine, and is preferably triphenylphosphine.
  • The phosphonic acid ester employed in the above reaction is not particularly restricted provided that it is generally used for the synthesis of the phosphonic acid ester, and can be, for example, a phosphonic acid ester indicated in the above-mentioned definition, and is preferably triethyl phosphonate.
  • The inert solvent employed in the above reaction is not particularly restricted provided that it has no adverse effect on the reaction, and can be, for example, an aliphatic hydrocarbon such as hexane or heptane; an aromatic hydrocarbon such as toluene or xylene; a halogenated hydrocarbon such as dichloromethane or 1,2-dichloroethane; an ester such as ethyl acetate or butyl acetate; an ether such as tetrahydrofuran, diethyl ether or t-butyl methyl ether; an amide such as 1-methyl-2-pyrrolidinone, N,N-dimethylformamide (DMF) or N,N-dimethylacetamide; an alcohol such as methanol, ethanol or n-propanol; a sulfoxide such as dimethyl sulfoxide; a nitrile such as acetonitrile, but depending on the reagent employed, the above reaction can be carried out in the absence of a solvent. The preferred inert solvent is ethyl acetate, DMF or acetonitrile.
  • The reaction temperature employed in the above reaction is different depending on the starting material, the reagent used and the sort of solvent, but is generally between - 20°C and 120°C, and preferably between 20°C and 100°C.
  • The reaction time employed in the above reaction is different depending on the reaction temperature, the starting material, the reagent used for the reaction and the sort of solvent employed, but is generally from 5 minutes to 48 hours, and preferably from 30 minutes to 10 hours.
  • After the reaction is completed, the desired compound of this reaction can be isolated from the reaction mixture and purified in the same manner as those described in the Method A.
    • Step F3
  • Step F3 is a process for the preparation of a compound having the general formula (Id') by reacting a compound having the general formula (V) with a compound having the general formula (VI) in the presence of a base in an inert solvent. Step F3 can be carried out in the same manner as that described in Step E1 of the method E.
  • The compound having the general formula (Id') obtained in Step F3 can be converted into a compound having the general formula (Id) in the same manner as that described in Step E2 of the Method E.
    • Method G
  • Method G is a process for the preparation of a compound having the general formula (IV') by reacting a compound having the general formula (IV") or salt thereof with a compound having the general formula (A) in the presence of a compound having the general formula (B) in a solvent.
    Figure imgb0039
  • In the above reaction scheme, R5, R6, R7, V, X and Y have the same meanings as those indicated hereinbefore.
  • The amount of the compound having the general formula (A) used is generally from 0.5 to 40.0 molar equivalents of the amount of the compound having the general formula (IV") or salt thereof used, and preferably from 1.0 to 10.0 molar equivalents.
  • The amount of the compound having the general formula (B) used is generally from 0.5 to 40.0 molar equivalents of the amount of the compound having the general formula (IV") or salt thereof used, and preferably from 1.0 to 10.0 molar equivalents.
  • The reaction of this Step is generally carried out in a solvent. The solvent employed in the above reaction can be, for example, an amide such as N,N-dimethylformamide, N,N-dimethylacetamide or N-methylpyrrolidone; a sulfoxide such as dimethyl sulfoxide; a halogenated hydrocarbon such as chloroform or dichloromethane; an aromatic hydrocarbon such as benzene or toluene; an aliphatic hydrocarbon such as hexane or cyclohexane; an ether such as tetrahydrofuran, dioxane, diethyl ether or dimethoxyethane; an ester such as methyl acetate or ethyl acetate; or a nitrile such as acetonitrile or propionitrile. These solvents may be used in the above reaction as mixtures containing at least two of them in any ratio.
  • The solvent employed in the above reaction is preferably a mixed solvent of an aromatic hydrocarbon and a nitrile and more preferably a mixed solvent of toluene and acetonitrile.
  • The reaction temperature employed in the above reaction is generally between -80°C and 150°C, and preferably between -20°C and 50°C.
  • The reaction time employed in the above reaction is generally from 1 minute to 240 hours, and preferably from 10 minutes to 120 hours.
  • The compound having the general formula (IV') or salt thereof thus obtained can be isolated and purified by any known procedures for isolation and purification, for example, through evaporation, concentration under reduced pressure, extraction with solvent, crystallization, recrystallization, partitioning between solvent systems, chromatography and the like.
    • [Examples]
  • The present invention is described in more detail hereinafter by way of the Examples and the Test examples, but the scope of the present invention should not be limited to these examples.
    • (Example 1) (2R,4S)-2-t-Butyl-4-methyl-1,3-oxazolidine-3,4-dicarboxylic acid dimethyl ester (compound shown as Ia in Table 1: Exemplification compound number 55)
  • Figure imgb0040
  • To a solution of (2R,4S)-2-t-butyl-1,3-oxazolidine-3,4-dicarboxylic acid dimethyl ester (384 g, 1.57 mol) prepared according to the procedure described in the literature (CHIMICA, 42, 176 (1988)) in tetrahydrofuran (2300 mL) were added successively tetraethylene glycol dimethyl ether (380 mL) and methyl iodide (290 mL, 4.70 mol) under a nitrogen atmosphere with stirring, and the resulting mixture was cooled to about -20°C. Subsequently, to the resulting mixture was added dropwise slowly a solution of potassium t-butoxide (263 g, 2.35 mol) in tetrahydrofuran (1900 mL) below -5°C under a nitrogen atmosphere with stirring, and the resulting mixture was stirred at about -10°C for 1 hour. After stirring, a 10% aqueous ammonium chloride solution was added to the reaction mixture with stirring to quench the reaction, and the resulting mixture was extracted with toluene. The extract separated was washed twice with a 5% aqueous sodium chloride solution and evaporated in vacuo to afford the crude product of the title compound (373 g (determined by HPLC), yield: 92 %,). The crude product thus obtained was used for the following reaction step without further purification. Additionally, it could be possible to obtain the pure title compound by purifying the crude product by chromatography on a silica gel column (eluent: a mixed solvent of ethyl acetate and hexane).
    [α]D 27-9.74 (c 1.001, MeOH).
    1H NMR (CDCL3,400MHz): δ 0.97 (s, 9H), 1.62 (s, 3H), 3.69 (s, 3H), 3.77 (s, 3H), 3.82 (d, 1H, J=8.3Hz), 4.28 (d, 1H, J=8.3Hz), 5.15 (s, 1H).
    13C NMR (CDCL3,100MHz): δ 21.2, 26.3, 39.0, 52.4, 52.6, 66.5, 76.9, 97.6, 155.1, 172.2.
    IR νmax (Liquid Film): 2958, 2909, 1737, 1719, 1478, 1443, 1345, 1313, 1282, 1249, 1218, 1195, 1141, 1115, 1059, 1034 cm-1.
    • (Example 2) (2R,4R)-2-t-Butyl-4-hydroxymethyl-4-methyl-l,3-oxazolidine-3-carboxylic acid methyl ester (compound shown as Ib in Table 2: Exemplification compound number 28)
  • Figure imgb0041
  • A mixture of lithium chloride (132 g, 3.13 mol), potassium borohydride (168 g, 3.13 mol) and tetrahydrofuran (3800 mL) was stirred at room temperature under a nitrogen atmosphere for 1 hour. Subsequently, to the mixture was added a solution of (2R,4S)-2-t-butyl-4-methyl-1,3-oxazolidine-3,4-dicarboxylic acid dimethyl ester (373 g, 1.44 mol) prepared according to the procedure described in Example 1 in toluene (1150 mL) under a nitrogen atmosphere with stirring, and the resulting mixture was warmed to about 45°C and furthermore stirred at the same temperature for 3 hours. After stirring, the reaction mixture was cooled in an ice-bath, and to the reaction mixture was added slowly a 10% aqueous ammonium chloride solution with stirring to quench the reaction. The reaction mixture was extracted with toluene, and the extract was washed with water and evaporated in vacuo to afford the crude product of the title compound (327 g (determined by HPLC), yield: 98 %,). The crude product thus obtained was used for the following reaction step without further purification. Additionally, it could be possible to obtain the pure title compound by purifying the crude product by chromatography on a silica gel column (eluent: a mixed solvent of ethyl acetate and hexane).
    [α]D 27+12.7 (c 1.009, MeOH).
    1H NMR (CDCL3, 400 MHz): δ 0.93 (s, 9H), 1.43 (s, 3H), 3.55 (brd, 1H, J=11.3Hz), 3.71 (s, 3H), 3.74 (d, 1H, J=8.6Hz), 3.83 (d, 1H, J=11.3Hz), 3.87 (brd, 1H, J=8.6Hz), 5.13 (s, 1H).
    13C NMR (CDCL3, 100MHz): δ 19.5, 26.4, 38.6, 52.5, 65.2, 67.1, 75.8, 97.3, 156.8. IR νmax (Liquid Film): 3440, 2959, 2909, 2875, 1709, 1686, 1479, 1447, 1399, 1358, 1317,1281,1196,1172,1134,1112,1069,1047,960,805,759 cm-1.
    • (Example 3) (2R,4S)-2-t-Butyl-4-formy-4-methyl-1,3-oxazolidine-3-carboxylic acid methyl ester (compound shown as Ic in Table 2: Exemplification compound number 28)
  • Figure imgb0042
  • To a solution of (2R,4S)-2-t-butyl-4-hydroxymethyl-4-methyl-1,3-oxazolidine-3-carboxylic acid methyl ester (260 g, 1.12 mol) prepared according to the procedure described in Example 2 in toluene (6000 mL) were added successively water (3000 mL), sodium bromide (128 g) and sodium hydrogencarbonate (260 g) with stirring, and the resulting mixture was cooled to about 0°C. Subsequently, to the resulting mixture was added 2,2,6,6-tetramethylpiperidinooxy, free radical (1.94 g, 0.0125 mol) with stirring, and furthermore, to the resulting mixture was added dropwise slowly a 12.7% aqueous sodium hypochlorite solution (748 mL, 1.34 mol) below 5°C with stirring, and the resulting mixture was furthermore stirred at about 0°C for 30 minutes. After stirring, ethanol was added to the reaction mixture with stirring, and the resulting mixture was stirred for about 1 hour, and then the reaction was quenched. After partitioning the reaction mixture, the organic layer separated was washed successively with an aqueous sodium thiosulfate solution and water, and evaporated in vacuo to afford the crude product of the title compound (225 g, yield: 87 %,). The crude product thus obtained was used for the following reaction step without further purification. Additionally, it could be possible to obtain the pure title compound by recrystallization of the crude product from hexane.
    [α]D 27-7.09 (c1.002, acetonitrile).
    1H NMR (CDCL3, 400MHz): δ 0.98 (s, 9H), 1.48(s, 3H), 3.67 (d, 1H, J=8.8Hz), 3.70 (s, 3H), 4.17 (d, 1H, J=8.8Hz), 5.20 (s, 1H), 9.72 (s,1H).
    13C NMR (CDCL3, 100MHz): δ 18.1, 26.3, 38.9, 52.7, 70.0, 73.1, 97.3, 155.6, 199.2.
    IR νmax (KBr): 2982, 2967, 2958, 2938, 2897, 2887, 1737, 1711, 1476, 1443, 1357, 1340, 1307, 1216, 1198, 1181, 1115, 1051, 995, 950, 937 cm-1.
    • (Example 4) (2R,4R)-2-t-Butyl-4-methyl-4-[2-(1-methyl-1H-pyrrol-2-yl)ethyl]-1,3-oxazolidine-3-carboxylic acid methyl ester (compound shown as Id in Table 3: Exemplification compound number 121)
  • Figure imgb0043
  • To a solution of (2R,4S)-2-t-butyl-4-formyl-4-methyl-1,3-oxazolidine-3-carboxylic acid methyl ester (225 g, 0.981 mol) prepared according to the procedure described in Example 3 in N,N-dimethylformamide (1125 mL) was added [(1-methyl-1H-pyrrol-2-yl)methyl]triphenylphosphonium iodide (522 g, 1.08 mol) prepared according the procedure described in the literature (J. Org. Chem., 52, 19 (1987) with stirring, and the resulting mixture was cooled to about -10°C. Subsequently, to the reaction mixture was added dropwise a solution of potassium t-butoxide (132 g, 1.18 mol) in dimethylformamide (125 mL) below 5°C with stirring, and the resulting mixture was stirred at about 0°C for about 1 hour. After stirring, water was added to the reaction mixture to quench the reaction, and the reaction mixture was extracted with heptane. The extract was evaporated in vacuo to afford the Wittig reaction product.
  • Subsequently, to a solution of the Wittig reaction product obtained above in methanol (2250 mL) was added 5% palladium-charcoal (45 g) with shaking, and the resulting mixture was shaken at room temperature under a hydrogen atmosphere for about 1.5 hours. After shaking, the reaction mixture was filtered through a membrane filter (pore diameter: 0.2 µm), and the filtrate was evaporated in vacuo. The residue obtained was recrystallized from a mixed solvent of methanol and water (1:1, v/v) to afford the almost pure title compound (278 g, yield: 92 %).
    [α]D 27-12.6 (c1.001, MeOH).
    1H NMR (CDCL3, 400MHz): δ 0.97 (s, 9H), 1.43 (s, 3H), 2.05 (apparent dt, 1H, J=4.3, 12.8Hz), 2.39 (apparent dt, 1H, J=4.1, 12.7Hz), 2.51 (ddd, 1H, J=4.4, 12.4, 14.6Hz), 2.61 (ddd, 1H, J=4.6, 12.6, 14.5Hz), 3.55 (s, 3H), 3.69 (s, 1H), 3.70 (d, 3H, J=8.3Hz), 4.00 (d, 1H, J=8.3Hz), 5.15 (s, 1H), 5.90 (brs, 1H), 6.05 (s, 1H), 6.53 (brs, 1H).
    13C NMR (DMSO-d6, 100MHz): δ 21.6, 22.1, 26.6, 33.2, 37.2, 38.3, 52.1, 63.7, 77.1, 96.5, 105.1, 106.3, 121.4, 132.3, 156.2.
    IR νmax (KBr): 2979, 2954, 2921, 2891, 1698, 1493, 1466, 1447, 1351, 1318, 1304, 1168, 1098, 1063, 958, 725 cm-1.
    • (Example 5) (2R,4S)-2-Isopropyl-4-methyl-1,3-oxazolidine-3,4-dicarboxylic acid dimethyl ester (compound shown as Ia in Table 1: Exemplification compound number 13)
  • Figure imgb0044
    • (i) (4S)-2-Isopropyl-1,3-oxazolidine-4-carboxylic acid methyl ester
  • To a suspension of L-serine methyl ester hydrochloride (50.00 g, 321 mmol) in toluene (500 mL) were added successively 2-methylpropanal (35.2 mL, 385 mmol), triethylamine (49.3 mL, 354 mmol) and water-absorbing polymer (2.50 g) under a nitrogen atmosphere with stirring, and the resulting mixture was stirred at 45°C for 2 hours under the nitrogen atmosphere. After cooling the reaction mixture to 25°C, the insoluble materials were filtered off, and the insoluble materials separated were washed with toluene (250 mL). The filtrate and the washings were combined and evaporated in vacuo to remove toluene, and the residue obtained was purified by distillation under reduced pressure to afford the title compound (97-98°C/10 mm Hg, 44.66 g, yield: 80 %).
    1H NMR (CDCl3, 400MHz): δ 0.94 (d, J=6.8Hz, 3H),1.01 (d, J=6.8Hz, 3H), 1.60-1.92 (m, 1H), 2.00-2.45 (m,1H), 3.72-3.80 (m,4H), 3.85-4.20 (m, 3H).
    MS (FAB): m/z 174 (M+H+).
    HRMS (FAB): calcd for C8H16NO3 (M+H+): 174.1130.
    found: 174.1127.
    • (ii) (2R,4S)-2-Isopropyl-1,3-oxazolidine-3,4-dicarboxylic acid dimethyl ester
  • A mixture of (4S)-2-i.sopropyl-1,3-oxazolidine-4-carboxylic acid methyl ester (28.22 g, 163 mmol) synthesized according to the procedure described in Step (i) and toluene (250 mL) was cooled to about 0°C under a nitrogen atmosphere with stirring. Subsequently, to the mixture was added dropwise methyl chloroformate (21.4 mL, 277 mmol) below 5°C with stirring under a nitrogen atmosphere, and the resulting mixture was stirred at about 0°C for 1 hour. After stirring, triethylamine (22.7 mL, 163 mmol) was added dropwise to the reaction mixture, and the resulting mixture was stirred at about 25°C for 1 hour. After stirring, water (100 mL) was added to the reaction mixture to quench the reaction, and the resulting mixture was partitioned. The organic layer separated was washed with water and evaporated in vacuo to afford the crude product of the title compound (47.25 g, yield: 125 %,). Additionally, it could be possible to obtain the pure title compound by purifying the crude product by chromatography on a silica gel column (eluent: a mixed solvent of ethyl acetate and hexane).
    1H NMR (CDCl3, 400MHz): δ 0.72 (d, J=6.8Hz, 3H), 0.97 (d, J=6.8Hz, 3H), 1.95-2.30 (m, 1H), 3.71 (s, 6H), 4.05-4.18 (m,2H), 4.38-4.62 (m, 1H), 4.85-5.07 (m, 1H).
    MS (FAB): m/z 232 (M+H+), 188,160.
    HRMS (ESI): calcd for C10H17NNaO5 (M+Na+): 254.1004. found: 254.1016.
    • (iii) (2R,4S)-2-Isopropyl-4-methyl-1,3-oxazolidine-3,4-dicarboxylic acid dimethyl ester
  • Following the procedure mentioned in Example 1, a similar reaction was carried out using (2R,4S)-2-isopropyl-1,3-oxazolidine-3,4-dicarboxylic acid dimethyl ester (36.31 g, 157 mmol) synthesized according to the procedure described in Step (ii) to afford the crude product of the title compound (38.22 g (determined by HPLC), yield: 99 %). Additionally, it could be possible to obtain the pure title compound in crystalline form (28.28 g, yield: 73 %) by replacing the solvent containing the crude title compound by IsoparE and adjusting the solvent volume to 135 mL, followed by cooling the solution containing the title compound to 0°C.
    1H NMR: (CDCl3, 400MHz) δ 0.92 (d, J=6.8Hz, 3H), 0.99 (d, J=6.8Hz, 3H), 1.59 (s, 3H), 2.10-2.58 (m, 1H), 3.37 (s, 3H), 3.55 (s, 3H), 3.78 (d, J=8.2Hz, 1H), 4.19 (d, J=8.2 Hz, 1H), 4.90-5.12 (m, 1H).
    MS (FAB): m/z 246 (M+H+), 202, 174.
    HRMS (ESI): calcd for C11H19NNaO5 (M+Na+): 268.1161. found: 268.1181.
    • (Example 6) (2R,4S)-2-Isopropyl-4-hydroxymethyl-4-methyl-1,3-oxazolidine-3-carboxylic acid methyl ester (compound shown as Ib in Table 2: Exemplification compound number 7)
  • Figure imgb0045
  • Following the procedure mentioned in Example 2, a similar reaction was carried out using (2R,4S)-2-isopropyl-4-methyl-1,3-oxazolidine-3,4-dicarboxylic acid dimethyl ester (10.00 g, 40.8 mmol) synthesized according to the procedure described in Example 5 to afford the crude product of the title compound (7.62 g (determined by HPLC), yield: 86 %). Additionally, it could be possible to obtain the pure title compound by purifying the crude product by chromatography on a silica gel column (eluent: a mixed solvent of ethyl acetate and hexane).
    1H NMR (CDCl3, 400MHz): δ 0.90 (d, J=6.8Hz, 3H), 0.99 (d, J=6.8Hz, 3H), 1.41 (s, 3H), 2.05-2.26 (m, 1H), 3.45-3.92 (m,7H), 5.00 (d, J=4.4Hz, 1H).
    MS (FAB): m/z 218 (M+H+), 186.
    HRMS (ESI): calcd for C10H19NNaO4 (M+Na+): 240.1212. found: 240.1183.
    • (Example 7) (2R,4S)-2-Isopropyl-4-formyl-4-methyl-1,3-oxazolidine-3-carboxylic acid methyl ester (compound shown as Ic in Table 2: Exemplification compound number 7)
  • Figure imgb0046
  • Following the procedure mentioned in Example 3, a similar reaction was carried out using (2R,4S)-2-isopropyl-4-hydroxymethyl-4-methyl-1,3-oxazolidine-3-carboxylic acid methyl ester (8.00 g, 36.8 mmol) synthesized according to the procedure described in Example 6 to afford the crude product of the title compound (7.13 g (determined by HPLC), yield: 90 %). Additionally, it could be possible to obtain the pure title compound by purifying the crude product by chromatography on a silica gel column (eluent: a mixed solvent of ethyl acetate and hexane).
    1H NMR (CDCl3, 400MHz) : δ 0.85 (d, J=6.8Hz, 3H), 0.93 (d, J=6.8Hz, 3H), 1.46 (s, 3H), 2.20-2.54 (m, 1H), 3.63 (d, J=7.2Hz, 1H), 3.72 (s, 3H), 4.07 (d, J=7.2Hz, 1H), 4.98-5.25 (m, 1H), 9.60 (s, 1H).
    MS (FAB): m/z 216 (M+H+), 186.
    HRMS (ESI): calcd for C10H17NNaO4(M+Na+): 238.1055. found: 238.1032.
    • (Example 8) (2R,4R)-2-Isopropyl-4-methyl-[2-(1-methyl-1H-pyrrol-2-yl)ethyl]-1,3-oxazolidine-3-carboxylic acid methyl ester (compound shown as Id in Table 3: Exemplification compound number 25)
  • Figure imgb0047
  • Following the procedure mentioned in Example 4, a similar reaction was carried out using (2R,4S)-2-isopropyl-4-formyl-4-methyl-1,3-oxazolidine-3-carboxylic acid methyl ester (20.80 g, 96.6 mmol) synthesized according to the procedure described in Example 7 to afford the crude product of the title compound (25.33 g (determined by HPLC), yield: 89 %). Additionally, it could be possible to obtain the pure title compound by purifying the crude product by chromatography on a silica gel column (eluent: a mixed solvent of ethyl acetate and hexane).
    1H NMR (DMSO-d6, 400MHz): δ 0.83 (d, J=6.8Hz, 3H), 0.91 (d, J=6.8Hz, 3H), 1.35 (s, 3H), 1.80-2.15 (m, 3H), 2.44-2.52 (m, 2H), 3.47 (s, 3H), 3.53-3.72 (m, 4H), 3.95 (d, J=8.4Hz, 1H), 4.90 (d, J=4.4Hz, 1H), 5.70-5.73 (m, 1H), 5.83-5.85 (m, 1H), 6.57-6.60 (m, 1H).
    MS (FAB): m/z 295 (M+H+), 148, 94.
    HRMS (FAB): calcd for C16H26N2O3: 294.1943. found: 294.1936.
    • (Example 9) (2R,4S)-2-Isopropyl-4-methyl-1,3-oxazolidine-3,4-dicarboxylic acid 3-t-butyl ester 4-methyl ester (compound shown as Ia in Table 1: Exemplification compound number 1)
  • Figure imgb0048
    • (i) (2R,4S)-2-Isopropyl-1,3-oxazolidine-3,4-dicarboxylic acid 3-t-butyl ester 4-methyl ester
  • A mixture of (4S)-2-isopropyl-1,3-oxazolidine-4-carboxylic acid methyl ester (30.00 g, 173 mmol) synthesized according to the procedure described in Example 5 (i), Boc2O (39.8 mL, 173 mL) and tetrahydrofuran (300 mL) was stirred at about 45°C for 4 hours. After stirring, the reaction mixture was cooled to about 25°C and evaporated in vacuo to afford the crude product of the title compound (45.93 g (determined by HPLC), yield: 97 %). Additionally, it could be possible to obtain the pure title compound by purifying the crude product by chromatography on a silica gel column (eluent : a mixed solvent of ethyl acetate and hexane).
    1H NMR (CDCl3, 400 MHz): δ 0.72 (d, J=6.8Hz, 3H), 0.97 (d, J=6.8Hz, 3H), 1.44 (s, 9H), 1.84-2.15 (m, 1H), 3.73 (s, 3H), 4.05-4.15 (m, 2H), 4.20-4.34 (m, 1H), 4.85-5.02 (m, 1H).
    MS (FAB): m/z 274 (M+H+), 218, 174, 146, 130.
    HRMS (ESI): calcd for C13H23NNaO5 (M+Na+): 296.1474. found: 296.1492.
    • (ii) (2R,4S)-2-Isopropyl-4-methyl-1,3-oxazolidine-3,4-dicarboxylic acid 3-t-butyl ester 4-methyl ester
  • Following the procedure mentioned in Example 1, a similar reaction was carried out using (2R,4S)-2-isopropyl-1,3-oxazolidine-3,4-dicarboxylic acid 3-t-butyl ester 4-methyl ester (45.93 g, 168 mmol) synthesized according to the procedure described in Step (i) to afford the crude product of the title compound (41.27 g (determined by HPLC), yield: 86 %). Additionally, it could be possible to obtain the pure title compound by purifying the crude product by chromatography on a silica gel column (eluent: a mixed solvent of ethyl acetate and hexane).
    1H NMR (CDCl3, 400MHz) : δ 0.85 (d, J=6.8Hz, 3H), 0.95 (d, J=6.8Hz, 3H), 1.41 (s, 9H), 1.57 (s, 3H), 2.20-2.53 (m,1H), 3.73 (s, 3H), 3.75 (d, J=8.3Hz, 1H), 4.14 (d, J=8.3Hz, 1H), 4.85-5.16 (m, 1H).
    MS (FAB): m/z 288 (M+H+), 232, 188, 144.
    HRMS (ESI): calcd for C14H25NNaO5 (M+Na+): 310.1630. found: 310.1604.
    • (Example 10) (2R,4S)-2-Isopropyl-4-hydroxymethyl-4-methyl-1,3-oxazolidine-3-carboxylic acid t-butyl ester (compound shown as Ib in Table 2: Exemplification compound number 1)
  • Figure imgb0049
  • Following the procedure mentioned in Example 2, a similar reaction was carried out using (2R,4S)-2-isopropyl-4-methyl-1,3-oxazolidine-3,4-dicarboxylic acid 3-t-butyl ester 4-methyl ester (41.27 g, 144 mmol) synthesized according to the procedure described in Example 9 to afford the crude product of the title compound (35.23 g (determined by HPLC), yield: 95 %). Additionally, it could be possible to obtain the pure title compound by purifying the crude product by chromatography on a silica gel column (eluent: a mixed solvent of ethyl acetate and hexane).
    1H NMR (CDCl3, 400MHz): δ 0.84 (d, J=6.8Hz, 3H), 0.93 (d, J=6.8Hz, 3H), 1.40 (s, 3H), 1.44 (s, 9H), 2.00-2.15 (m, 1H), 3.38-3.82 (m, 4H), 4.90-4.98 (m, 1H).
    MS (FAB): m/z 260 (M+H+), 204,132.
    HRMS (ESI): calcd for C13H25NNaO4(M+Na+): 282.1681. found: 282.1682.
    • (Example 11) (2R,4S)-2-Isopropyl-4-formyl-4-methyl-1,3-oxazolidine-3-carboxylic acid t-butyl ester (compound shown as Ic in Table 2: Exemplification compound number 1)
  • Figure imgb0050
  • Following the procedure mentioned in Example 3, a similar reaction was carried out using (2R,4S)-2-isopropyl-4-hydroxymethyl-4-methyl-1,3-oxazolidine-3-carboxylic acid t-butyl ester (35.23 g, 136 mmol) synthesized according to the procedure described in Example 10 to afford the crude product of the title compound (24.80 g (determined by HPLC), yield: 71 %). Additionally, it could be possible to obtain the pure title compound by purifying the crude product by chromatography on a silica gel column (eluent: a mixed solvent of ethyl acetate and hexane).
    1H NMR (CDCl3, 400MHz): δ 0.89 (d, J=6.8Hz, 3H), 0.98 (d, J=6.8Hz, 3H), 1.42 (s, 9H), 1.45 (s, 3H), 2.10-2.55 (m, 1H), 3.61 (d, J=8.2Hz, 1H), 4.04 (d, J=8.2Hz, 1H), 4.85-5.18 (m, 1H), 9.55 (s, 1H).
    MS (FAB): m/z 258 (M+H+), 202,130.
    HRMS (FAB): calcd for C13H24NO4 (M+H+): 258.1705.
    found: 258.1709.
    • (Example 12) (2R,4R)-2-Isopropyl-4-methyl-4-[2-(1-methyl-1H-pyrrol-2-yl)ethyl]-1,3-oxazolidine-3-carboxylic acid t-butyl ester (compound shown as Id in Table 3: Exemplification compound number 1)
  • Figure imgb0051
  • Following the procedure mentioned in Example 4, a similar reaction was carried out using (2R,4S)-2-isopropyl-4-formyl-4-methyl-1,3-oxazolidine-3-carboxylic acid t-butyl ester (8.00 g, 31.1 mmol) synthesized according to the procedure described in Example 11 to afford the crude product of the title compound (10.17 g (determined by HPLC), yield: 97 %). Additionally, it could be possible to obtain the pure title compound by purifying the crude product by chromatography on a silica gel column (eluent: a mixed solvent of ethyl acetate and hexane).
    1H NMR : (DMSO-d6, 400MHz) : δ 0.83 (d, J=6.8Hz, 3H), 0.93 (d, J=6.8Hz, 3H), 1.35 (s, 3H), 1.41 (s, 9H), 1.80-2.15 (m, 3H), 2.43-2.53 (m, 2H), 3.37 (s, 3H), 3.58 (d, J=7.6Hz, 1H), 3.94 (d, J=7.6Hz, 1H), 4.85 (d, J=4.4Hz, 1H), 5.71-5.74 (m, 1H), 5.82-5.86 (m, 1H), 6.57-6.60 (m, 1H).
    MS (FAB): m/z 336(M+), 281, 148, 94.
    HRMS (ESI): calcd for C19H32N2NaO3 (M+Na+): 359.2311. found: 359.2292.
    • (Example 13) (2R,4S)-2-(2-Ethylpropyl)-4-methyl-1,3-oxazolidine-3,4-dicarboxylic acid dimethyl ester (compound shown as Ia in Table 1: Exemplification compound number 97)
  • Figure imgb0052
    • (i) (4S)-2-(2-Ethylpropyl)-1,3-oxazolidine-4-carboxylic acid methyl ester
  • To a suspension ofL-serine methyl ester hydrochloride (50.00 g, 321 mmol) in toluene (500 mL) were added successively 2-ethylpropanal (47.5 mL, 386 mmol), triethylamine (49.3 mL, 354 mmol) and water-absorbing polymer (2.50 g) under a nitrogen atmosphere with stirring, and the resulting mixture was stirred at 45°C for 2 hours under the nitrogen atmosphere. After cooling the reaction mixture to 25°C, the insoluble materials were filtered off, and the insoluble materials were washed with toluene (250 mL). The filtrate and the washings were combined and evaporated in vacuo to afford the crude product of the title compound (55.83 g, yield: 86 %).
    1H NMR (CDCl3, 400MHz): δ 0.83-0.93 (m, 9H), 1.28-1.59 (m, 4H), 2.45-2.55 (m, 1H), 3.66-3.98 (m, 3H), 4.02-4.46 (m, 2H).
    MS (FAB): m/z 202 (M+H+), 200,130.
    HRMS (ESI): calcd for C10H19NNaO3 (M+Na+): 224.1263. found: 224.1262.
    • (ii) (2R,4S)-2-(2-Ethylpropyl)-1,3-oxazolidine-3,4-dicarboxylic acid dimethyl ester
  • Following the procedure mentioned in Example 5 (ii), a similar reaction was carried out using (4S)-2-(2-ethylpropyl)-1,3-oxazolidine-4-carboxylic acid methyl ester (5.00 g, 24.8 mmol) synthesized according to the procedure described in Step (i) to afford the crude product of the title compound. The crude product thus obtained was purified by chromatography on a silica gel column (eluent: a mixed solvent of ethyl acetate and hexane) to afford the pure title compound (5.21 g, yield: 81 %).
    1H NMR (CDCl3, 400MHz): δ 0.70 (t, J=7.6Hz, 3H), 0.86 (t, J=7.6Hz, 3H), 1.15-1.95 (m, 5H), 3.71 (s, 3H), 3.74 (s, 3H), 4.04-4.19 (m, 2H), 4.40-4.64 (m, 1H), 5.05-5.18 (m, 1H).
    MS (FAB): m/z 260 (M+H+), 188, 160.
    HRMS (ESI): calcd for C12H21NNaO5 (M+Na+): 282.1317. found: 282.1327.
    • (iii) (2R,4S)-2-(2-Ethylpropyl)-4-methyl-1,3-oxazolidine-3,4-dicarboxylic acid dimethyl ester
  • Following the procedure mentioned in Example 1, a similar reaction was carried out using (2R,4S)-2-(2-ethylpropyl)-1,3-oxazolidine-3,4-dicarboxylic acid dimethyl ester (5.21 g, 20.1 mmol) synthesized according to the procedure described in Step (ii) to afford the crude product of the title compound. The crude product thus obtained was purified by the reverse phase chromatography (eluent: a mixed solvent of acetonitrile and water) to afford the pure title compound (5.09 g, yield: 93 %).
    1H NMR (CDCl3, 400MHz): δ 0.89 (t, J=7.6Hz, 3H), 0.95 (t, J=7.6Hz, 3H), 1.15-1.70 (m, 7H), 1.78-2.13 (m,1H), 3.69 (s, 3H), 3.73-3.78 (m, 4H), 4.20 (d, J=8.5Hz, 1H),
    5.18-5.29 (m,1H).
    MS (FAB): m/z 274 (M+H+), 202,174.
    HRMS (ESI): calcd for C13H23NNaO5 (M+Na+): 296.1474. found: 296.1489.
    • (Example 14) (2R,4S)-2-(2-Ethylpropyl)-4-hydroxymethyl-4-methyl-1,3-oxazolidine-3-carboxylic acid methyl ester (compound shown as Ib in Table 2: Exemplification compound number 49)
  • Figure imgb0053
  • Following the procedure mentioned in Example 2, a similar reaction was carried out using (2R,4S)-2-(2-ethylpropyl)-4-methyl-1,3-oxazolidine-3,4-dicarboxylic acid dimethyl ester (5.09 g, 18.6 mmol) synthesized according to the procedure described in Example 13 to afford the crude product of the title compound. The crude product thus obtained was purified by the reverse phase chromatography (eluent: a mixed solvent of acetonitrile and water) to afford the pure title compound (3.35 g, yield: 73 %).
    1H NMR (CDCl3, 400MHz): δ 0.70 (t, J=7.6Hz, 3H), 0.84 (t, J=7.6Hz, 3H), 1.12-1.70 (m, 7H), 1.90-2.25 (m, 1H), 3.40-3.82 (m, 7H), 5.20 (d, J=4.0Hz, 1H).
    MS (FAB): m/z 246 (M+H+), 174,146.
    HRMS (ESI): calcd for C12H23NNaO4(M+Na+): 268.1525. found: 268.1539.
    • (Example 15) (2R,4S)-2-(2-Ethylpropyl)-4-formyl-4-methyl-1,3-oxazolidine-3-carboxylic acid methyl ester (compound shown as Ic in Table 2: Exemplification compound number 49)
  • Figure imgb0054
  • Following the procedure mentioned in Example 3, a similar reaction was carried out using (2R,4S)-2-(2-ethylpropyl)-4-hydroxymethyl-4-methyl-1,3-oxazolidine-3-carboxylic acid methyl ester (3.00 g, 12.2 mmol) synthesized according to the procedure described in Example 14 to afford the crude product of the title compound. The crude product thus obtained was purified by chromatography on a silica gel column (eluent : a mixed solvent of ethyl acetate and hexane) to afford the pure title compound (2.55 g, yield: 86 %).
    1H NMR (CDCl3, 400MHz) : δ 0.73 (t, J=7.6Hz, 3H), 0.80 (t, J=7.6Hz, 3H), 1.12-1.56 (m, 7H), 1.85-2.12 (m, 1H), 3.62 (d, J=8.8Hz, 1H), 3.71 (s, 3H), 4.10 (d, J=8.8Hz, 1H), 5.15-5.34 (m, 1H), 9.63 (s, 1H).
    MS (FAB): m/z 244 (M+H+), 144.
    HRMS (ESI): calcd for C12H23NNaO4(M+Na+): 266.1368. found: 266.1378.
    • (Example 16) (2R,4R)-2-(2-Ethylpropyl)-4-methyl-4-[2-(1-methyl-1H-pyrrol-2-yl)ethyl]-1,3-oxazolidine-3-carboxylic acid methyl ester (compound shown as Id in Table 3: Exemplification compound number 265)
  • Figure imgb0055
  • Following the procedure mentioned in Example 4, a similar reaction was carried out using (2R,4S)-2-(2-ethylpropyl)-4-formyl-4-methyl-1,3-oxazolidine-3-carboxylic acid methyl ester (2.00 g, 8.2 mmol) synthesized according to the procedure described in Example 15 to afford the crude product of the title compound. The crude product thus obtained was purified by reverse phase chromatography (eluent: a mixed solvent of acetonitrile and water) to afford the pure title compound (2.04 g, yield: 77 %).
    1H NMR (DMSO-d6, 400MHz): δ 0.85 (d, J=7.6Hz, 3H), 0.91 (d, J=7.6Hz, 3H), 1.15-1.50 (m, 7H), 1.85-2.14 (m, 3H), 2.44-2.54 (m, 2H), 3.48 (s, 3H), 3.56-3.61 (m, 4H), 3.94 (d, J=8.8Hz, 1H), 5.09 (d, J=4.4Hz, 1H), 5.69-5.73 (m, 1H), 5.83-5.86 (m, 1H), 6.56-6.60 (m, 1H).
    MS (FAB): m/z 323 (M+H+), 148.
    HRMS (ESI): calcd for C18H31N2O3 (M+H+): 323.2335. found: 323.2349.
    • (Example 17) (2R,4S)-2-(2-Ethylpropyl)-4-hydroxymethyl-4-methyl-1,3-oxazolidine-3-carboxylic acid t-butyl ester (compound shown as Ia in Table 1: Exemplification compound number 85)
  • Figure imgb0056
    • (i) (2R,4S)-2-(2-Ethylpropyl)-1,3-oxazolidine-3,4-dicarboxylic acid 3-t-butyl ester 4-methyl ester
  • Following the procedure mentioned in Example 9 (i), a similar reaction was carried out using (4S)-2-(2-ethylpropyl)-1,3-oxazolidine-4-carboxylic acid methyl ester (5.00 g, 24.8 mmol) synthesized according to the procedure described in Example 13(i) to afford the crude product of the title compound. The crude product thus obtained was purified by chromatography on a silica gel column (eluent: a mixed solvent of ethyl acetate and hexane) to afford the pure title compound (6.52 g, yield: 87 %).
    1H NMR (CDCl3, 400MHz): δ 0.69 (t, J=7.6Hz, 3H), 0.75 (t, J=7.6Hz, 3H), 1.15-1.95 (m, 14H), 3.74 (s, 3H), 4.04-4.10 (m, 2H), 4.34-4.68 (m, 1H), 5.01-5.20 (m, 1H).
    MS (FAB): m/z 302 (M+H+), 246, 146.
    HRMS (ESI): calcd for C15H27NNaO5 (M+Na+): 324.1787. found: 324.1801.
    • (ii) (2R,4S)-2-(2-Ethylpropyl)-4-methyl-1,3-oxazolidine-3,4-dicarboxylic acid 3-t-butyl ester 4-methyl ester
  • Following the procedure mentioned in Example 1, a similar reaction was carried out using (2R,4S)-2-(2-ethylpropyl)-1,3-oxazolidine-3,4-dicarboxylic acid 3-t-butyl ester 4-methyl ester (4.00 g, 13.3 mmol) synthesized according to the procedure described in Step (i) to afford the crude product of the title compound. The crude product thus obtained was purified by chromatography on a silica gel column (eluent: a mixed solvent of ethyl acetate and hexane) to afford the pure title compound (3.35 g, yield: 80 %).
    1H NMR (CDCl3, 400MHz): δ 0.75 (t, J=7.6Hz, 3H), 0.86 (t, J=7.6Hz, 3H), 1.02-2.02 (m, 17H), 3.59-3, 63 (m, 4H), 4.14 (d, J=8.3Hz, 1H), 5.13-5.27 (m, 1H).
    MS (FAB): m/z 316 (M+H+), 216, 214.
    HRMS (ESI): calcd for C16H29NNaO5 (M+Na+): 338.1943. found: 338.1960.
    • (Example 18) (2R,4S)-2-(2-Ethylpropyl)-4-hydroxymethyl-4-methyl-1,3-oxazolidine-3-carboxylic acid t-butyl ester (compound shown as Ib in Table 2: Exemplification compound number 43)
  • Figure imgb0057
  • Following the procedure mentioned in Example 2, a similar reaction was carried out using (2R,4S)-2-(2-ethylpropyl)-4-methyl-1,3-oxazolidine-3,4-dicarboxylic acid 3-t-butyl ester 4-methyl ester (2.50 g, 8.0 mmol) synthesized according to the procedure described in Example 17 to afford the crude product of the title compound. The crude product thus obtained was purified by reverse phase chromatography (eluent: a mixed solvent of acetonitrile and water) to afford the pure title compound (2.17 g, yield: 95 %).
    1H NMR (CDCl3, 400MHz): δ 0.89 (t, J=7.6Hz, 3H), 0.95 (t, J=7.6Hz, 3H), 1.14-2.04 (m, 17H), 3.50-3.79 (m, 4H), 5.18 (d, J=3.3Hz, 1H).
    MS (FAB): m/z 288 (M+H+), 232, 132.
    HRMS (ESI): calcd for C15H29NNaO4(M+Na+): 310.1994. found: 310.1992.
    • (Example 19) (2R,4S)-2-(2-Ethylpropyl)-4-formyl-4-methyl-1,3-oxazolidine-3-carboxylic acid t-butyl ester (compound shown as Ic in Table 2: Exemplification compound number 43)
  • Figure imgb0058
  • Following the procedure mentioned in Example 3, a similar reaction was carried out using (2R,4S)-2-(2-ethylpropyl)-4-hydroxymethyl-4-methyl-1,3-oxazolidine-3-carboxylic acid t-butyl ester (1.50 g, 5.2 mmol) synthesized according to the procedure described in Example 18 to afford the crude product of the title compound. The crude product thus obtained was purified by chromatography on a silica gel column (eluent: a mixed solvent of ethyl acetate and hexane) to afford the pure title compound (1.30 g, yield: 87 %).
    1H NMR (CDCl3, 400MHz): δ 0.75 (t, J=7.6Hz, 3H), 0.84 (t, J=7.6Hz, 3H), 1.03-2.13 (m, 17H), 3.59 (d, J=9.0Hz, 1H), 4.02 (d, J=9.0Hz, 1H), 5.12-5.33 (m, 1H), 9.60 (s, 1H).
    MS (FAB): m/z 286 (M+H+), 230, 130.
    HRMS (ESI): calcd for C15H27NNaO4 (M+Na+): 308.1838. found: 308.1853.
    • (Example 20) (2R,4R)-2-(2-Ethylpropyl)-4-methyl-4-[2-(1-methyl-1H-pyrrol-2-yl)ethyl]-1,3-oxazolidine-3-carboxylic acid t-butyl ester (compound shown as Id in Table 3: Exemplification compound number 241)
  • Figure imgb0059
  • Following the procedure mentioned in Example 4, a similar reaction was carried out using (2R,4S)-2-(2-ethylpropyl)-4-formyl-4-methyl-1,3-oxazolidine-3-carboxylic acid t-butyl ester (1.00 g, 3.5 mmol) synthesized according to the procedure described in Example 19 to afford the crude product of the title compound. The crude product thus obtained was purified by reverse phase chromatography (eluent: a mixed solvent of acetonitrile and water) to afford the pure title compound (1.01 g, yield: 79 %).
    1H NMR (DMSO-d6, 400MHz): δ 0.83 (d, J=7.6Hz, 3H), 0.91 (d, J=7.6Hz, 3H), 1.10-1.48 (m, 16H), 1.80-2.03 (m, 3H), 2.45-2.53 (m, 2H), 3.48 (s, 3H), 3.56 (d, J=8.6Hz, 1H), 3.92 (d, J=8.6Hz, 1H), 5.04 (d, J=4.0Hz, 1H), 5.68-5.72 (m, 1H), 5.83-5.86 (m, 1H), 6.56-6.60 (m, 1H).
    MS (FAB): m/z 365 (M+H+), 309, 148, 94.
    HRMS (ESI): calcd for C21H37N2O3 (M+H+): 365.2804. found: 365.281.
    • (Example 21) [(1-Methyl-1H-pyrrol-2-yl)methyl](triphenyl)phosphonium chloride
  • Figure imgb0060
  • To a suspension of triphenylphosphine (3.83 g, 14.6 mmol) in acetonitrile (17 mL) was added acetyl chloride (1.04 mL, 14.6 mmol) under ice-cooling with stirring. Subsequently, to the resulting mixture was added dropwise slowly a solution of 1-methyl-2-(pyrrolidin-1-ylmethyl)-1H-pyrrole (2.00 g, 12.2 mmol) synthesized by the procedure described in the literature (J. Am. Chem. Soc. 73, 4921 (1951)) in toluene (17 mL) below 5°C with stirring, and the resulting mixture was stirred under ice-cooling for 2 hours. After stirring, the precipitate formed was collected by filtration to afford the almost pure title compound (4.74 g, yield: 99 %).
    1H NMR (DMSO-d6, 400MHz): δ 2.96 (s, 3H), 5.27 (d, 2H, JPH=13.5Hz), 5.59 (d, 1H, J=1.7Hz), 5.91 (dd, 1H, J=1.7, 1.7Hz), 6.69 (d, 1H, J=1.7Hz), 7.60-8.00 (m, 15H). 13C NMR (DMSO-d6, 100MHz): δ 20.5, 21.0, 33.1, 107.6, 107.6, 110.8, 110.9, 116.7, 116.8, 117.6, 118.5, 123.8, 123.8, 130.0, 130.1, 133.8, 133.9, 135.1, 135.1.
    IR νmax (KBr): 3116, 3098, 3077, 3054, 3001, 2992, 2866, 2837, 2765, 1486, 1437, 1306, 1143, 1108, 998, 745, 736, 716, 692, 520, 505, 486 cm-1.
  • Additionally, following the procedure mentioned above, a similar reaction was carried out using 1-methyl-2-(N,N-dimethylaminomethyl)-1H-pyrrole, 1-methyl-2-(N,N-diethylaminomethyl)-1H-pyrrole and 1-methyl-2-(piperidin-1-ylmethyl)-1H-pyrrole as the starting materials instead of 1-methyl-2-(pyrrolidin-1-yhnethyl)-1H-pyrrole, and propionyl chloride or isobutyloyl chloride as the reagent instead of acetyl chloride to afford the title compound in the same yield.
    • (Example 22) (4-Methoxybenzyl)(triphenyl)phosphonium iodide
  • Figure imgb0061
  • To a suspension of triphenylphosphine (4.92 g, 18.8 mmol) in acetonitrile (10 mL) was added acetyl chloride (1.34 mL, 18.8 mmol) at room temperature with stirring, and the resulting mixture was warmed to about 50°C. Subsequently, to the reaction mixture was added dropwise slowly a solution of 1-(4-methoxybenzyl)pyrrolidine (1.00 g, 5.23 mmol) in toluene (10 mL) below 60°C with stirring, and the resulting mixture was stirred at about 50°C for 72 hours. After cooling the reaction mixture to room temperature, water (20 mL) and n-hexane (10 mL) were added to the reaction mixture, and the resulting mixture was partitioned. To the aqueous layer separated were added successively water (10 mL) and sodium iodide (0.94 g, 6.28 mmol) with stirring, and the resulting mixture was stirred under ice-cooling for 1 hour. After stirring, the precipitate formed was collected by filtration to afford the almost pure title compound (2.31 g, yield: 87 %).
    1H NMR (DMSO-d6, 400MHz): δ 3.70 (s, 3H), 5.14 (d, 2H, JPH=32.0Hz), 6.70-7.00 (m, 4H), 7.60-8.00 (m, 15H).
    13C NMR (DMSO-d6, 100MHz): δ 27.2, 27.7, 55.1, 114.2, 114.2, 117.4, 118.3, 119.0, 119.0, 130.0, 130.1, 131.9, 132.0, 133.9, 134.0, 135.0, 135.0, 159.1, 159.1.
    IR νmax (KBr): 3036, 3005, 2962, 2882, 2854, 2787, 1610, 1584, 1512, 1439, 1254, 1178, 1112, 1030, 836, 740, 719, 688, 510 cm-1.
    • (Example 23) Triphenyl(thien-2-ylmethyl)phosphonium iodide
  • Figure imgb0062
  • To a suspension of triphenylphosphine (6.66 g, 25.5 mmol) in acetonitrile (10 mL) was added acetyl chloride (1.80 mL, 25.5 mmol) at room temperature with stirring, and the resulting mixture was warmed to about 50°C. Subsequently, to the reaction mixture was added dropwise slowly a solution of 2-(dimethylaminomethyl)thiophene (1.00 g, 7.08 mmol) in toluene (10 mL) below 60°C with stirring, and the resulting mixture was stirred at about 50°C for 75 hours. After cooling the reaction mixture to room temperature, water (20 mL) and n-hexane (10 mL) were added to the reaction mixture, and the resulting mixture was partitioned. To the aqueous layer separated were added successively water (10 mL) and sodium iodide (1.27 g, 8.50 mmol) with stirring, and the resulting mixture was stirred under ice-cooling for 1 hour. After stirring, the precipitate formed was collected by filtration to afford the almost pure title compound (2.94 g, yield: 85 %).
    1H NMR (DMSO-d6, 400MHz): δ 5.51 (d, 2H, JPH=14.6Hz), 6.70-6.80 (m, 1H), 6.90-7.00 (m, 1H), 7.40-7.50 (m, 1H), 7.60-8.00 (m, 15H).
    13C NMR (DMSO-d6, 100MHz): δ 23.7, 24.2, 117.3, 118.1, 127.3, 127.4, 127.9, 127.9, 128.3, 128.4, 130.1, 130.2, 130.4, 130.5, 133.9, 134.0, 135.2, 135.2.
    IR νmax (KBr): 3065, 3046, 3004, 2986, 2867, 2829, 1585, 1484, 1435, 1161, 1109, 995, 860, 754, 742, 720, 690, 516, 498 cm-1.
    • (Example 24) [(5-Methyl-2-furyl)methyl](triphenyl)phosphonium iodide
  • Figure imgb0063
  • To a suspension of triphenylphosphine (6.79 g, 25.9 mmol) in acetonitrile (10 mL) was added acetyl chloride (1.84 mL, 25.9 mmol) at room temperature with stirring, and the resulting mixture was warmed to about 50°C. Subsequently, to the reaction mixture was added dropwise slowly a solution of N,N,5-trimethylfurfurylamine (1.00 g, 7.18 mmol) in toluene (10 mL) below 60°C with stirring, and the resulting mixture was stirred at about 50°C for 72 hours. After cooling the reaction mixture to room temperature, water (20 mL) and n-hexane (10 mL) were added to the reaction mixture, and the resulting mixture was partitioned. To the aqueous layer separated were added successively water (10 mL) and sodium iodide (1.29 g, 8.61 mmol) with stirring, and the resulting mixture was stirred under ice-cooling for 1 hour. After stirring, the precipitate formed was collected by filtration to afford the almost pure title compound
    (3.20 g, yield: 92 %).
    1H NMR (DMSO-d6, 400MHz): δ 2.04 (s, 3H), 5.32 (d, 2H, JPH=14.5Hz), 5.95-6.05 (m, 2H), 7.60-8.00 (m, 15H).
    13C NMR (DMSO-d6, 100MHz): δ 13.0, 22.7, 23.2, 107.3, 107.3, 112.8, 112.9, 117.5, 118.4, 130.0, 130.1, 133.8, 133.9, 135.1, 135.1, 139.5, 139.6, 152.6, 152.7.
    IR νmax (KBr): 3050, 3007, 2988, 2871, 2832, 2770, 1715, 1611, 1586, 1561, 1484, 1437, 1143, 1111, 1023, 996, 943, 799, 745, 732, 689, 522, 504, 485 cm-1.
    • [Possibility of industrial use]
  • The present invention is useful for providing optically active 4,4-di-substituted oxazolidine derivatives and procedures for their preparation. The preparation procedures of the present invention have excellent advantages in the following respects, compared with the prior art: 1) increase in yield, 2) improvement in stereoselectivity, 3) extremely low-temperature reaction which is unsuitable for industrial large-scale synthesis is not necessary, and 4) column-chromatographic purification of intermediates is not needed in any step of these synthetic processes.
  • Furthermore, the compounds having the general formula (Id), which are optically active 4,4-di-substituted oxazolidine derivatives encompassed in the present invention, are useful as the synthetic intermediates in the preparation of optically active α,α-di-substituted α-amino acid derivatives having an excellent glutamate receptor antagonistic action or optically active α,α-di-substituted amino alcohol derivatives having new immunosuppressive action.
  • Additionally, according to the present invention, the substituted methylenephosphonium salt which is useful as a synthetic intermediate in the preparation of compounds having the general formula (Id) and various kinds of medicines can be obtained conveniently in a high yield.

Claims (39)

  1. An optically active 4,4-di-substituted oxazolidine derivative having the general formula (I)
    Figure imgb0064
     [wherein,
    R1 represents a C1-C3 alkyl group which is substituted with one substituent selected from Substituent group A, a C2-C3 alkenyl group which is substituted with one substituent selected from Substituent group A, a halogenated methyl group, a hydroxymethyl group, a formyl group, a group of formula COOR or a phosphonium methyl group,
    R represents a C1-C6 alkyl group, a C2-C6 alkenyl group, a phenyl group or a benzyl group,
    R2 represents a C1-C6 alkyl group, a C3-C10 cycloalkyl group or a phenyl group,
    R3 represents a C2-C6 alkanoyl group, a C1-C6 alkyloxycarbonyl group, a benzoyl group, a phenyloxycarbonyl group or a benzyloxycarbonyl group,
    R4 represents a C1-C6 alkyl group or a C2-C6 alkenyl group,
    Substituent group A represents a phenyl group which may optionally be substituted with from 1 to 3 substituents selected from the group consisting of a halogen atom, a cyano group, a phenyl group, a C1-C8 alkyl group, a C1-C8 alkoxy group and a C2-C8 alkanoyl group, a thienyl group, a N-methylpyrrolyl group, or a furanyl group].
  2. An optically active 4,4-di-substituted oxazolidine derivative having the general formula (I) according to Claim 1, wherein R1 represents a formyl group.
  3. An optically active 4,4-di-substituted oxazolidine derivative having the general formula (I) according to Claim 1, wherein R1 represents a hydroxymethyl group.
  4. An optically active 4,4-di-substituted oxazolidine derivative having the general formula (I) according to Claim 1, wherein R1 represents a group of formula COOR, and R represents a C1-C4 alkyl group, an allyl group, a phenyl group or a benzyl group.
  5. An optically active 4,4-di-substituted oxazolidine derivative having the general formula (I) according to Claim 1, wherein R1 represents a methoxycarbonyl group or an ethoxycarbonyl group.
  6. An optically active 4,4-di-substituted oxazolidine derivative having the general formula (I) according to Claim 1, wherein R1 represents an ethyl group or a vinyl group both of which are substituted with one substituent selected from the group consisting of a 4-bromophenyl group, a 4-iodophenyl group, a 4-octylphenyl group, a 4-heptyloxyphenyl group, a 4-octanoylphenyl group, a thienyl group and a N-methylpyrrolyl group.
  7. An optically active 4,4-di-substituted oxazolidine derivative having the general formula (I) according to Claim 1, wherein R1 represents an ethyl group or a vinyl group both of which are substituted with a N-methylpyrrolyl group.
  8. An optically active 4,4-di-substituted oxazolidine derivative having the general formula (I) according to any one claim selected from Claim 1 to Claim 7, wherein R2 represents an isopropyl group, a t-butyl group, a diethylmethyl group, a cyclohexyl group or an adamantyl group.
  9. An optically active 4,4-di-substituted oxazolidine derivative having the general formula (I) according to any one claim selected from Claim 1 to Claim 7, wherein R2 represents a t-butyl group.
  10. An optically active 4,4-di-substituted oxazolidine derivative having the general formula (I) according to any one claim selected from Claim 1 to Claim 9, wherein R3 represents an acetyl group, a methoxycarbonyl group, an ethoxycarbonyl group, a t-butoxycarbonyl group, a phenyloxycarbonyl group or a benzyloxycarbonyl group.
  11. An optically active 4,4-di-substituted oxazolidine derivative having the general formula (I) according to any one claim selected from Claim 1 to Claim 10, wherein R3 represents a methoxycarbonyl group.
  12. An optically active 4,4-di-substituted oxazolidine derivative having the general formula (I) according to any one claim selected from Claim 1 to Claim 11, wherein R4 represents a methyl group.
  13. Any one of the optically active 4,4-di-substituted oxazolidine derivatives having the general formula (I) according to Claim 1 selected from following compounds:
    2-t-butyl-4-methyl-1,3-oxazolidine-3,4-dicarboxylic acid 3-t-butyl ester 4-methyl ester,
    2-t-butyl-4-methyl-1,3-oxazolidine-3,4-dicarboxylic acid 3-benzyl ester 4-methyl ester,
    2-t-butyl-4-methyl-1,3-oxazolidine-3,4-dicarboxylic acid dimethyl ester,
    2-t-butyl-4-methyl-1,3-oxazolidine-3,4-dicarboxylic acid 3-ethyl ester 4-methyl ester,
    3-acetyl-2-t-butyl-4-methyl-1,3-oxazolidine-4-carboxylic acid methyl ester,
    2-t-butyl-4-methyl-1,3-oxazolidine-3,4-dicarboxylic acid 3-phenyl ester 4-methyl ester,
    3-benzoyl-2-t-butyl-4-methyl-1,3-oxazolidine-4-carboxylic acid methyl ester,
    2-t-butyl-4-hydroxymethyl-4-methyl-1,3-oxazolidine-3-carboxylic acid t-butyl ester,
    2-t-butyl-4-hydroxymethyl-4-methyl-1,3-oxazolidine-3-carboxylic acid benzyl ester,
    2-t-butyl-4-hydroxymethyl-4-methyl-1,3-oxazolidine-3-carboxylic acid methyl ester,
    2-t-butyl-4-hydroxymethyl-4-methyl-1,3-oxazolidine-3-carboxylic acid ethyl ester,
    (3-acetyl-2-t-butyl-4-methyl-1,3-oxazolidin-4-yl)methanol,
    2-t-butyl-4-hydroxymethyl-4-methyl-1,3-oxazolidine-3-carboxylic acid phenyl ester,
    (3-benzoyl-2-t-butyl-4-methyl-1,3-oxazolidin-4-yl)methanol,
    2-t-butyl-4-formyl-4-methyl-1,3-oxazolidine-3-carboxylic acid t-butyl ester,
    2-t-butyl-4-formyl-4-methyl-1,3-oxazolidine-3-carboxylic acid benzyl ester,
    2-t-butyl-4-formyl-4-methyl-1,3-oxazolidine-3-carboxylic acid methyl ester,
    2-t-butyl-4-formyl-4-methyl-1,3-oxazolidine-3-carboxylic acid ethyl ester,
    3-acetyl-2-t-butyl-4-methyl-1,3-oxazolidine-4-carbaldehyde,
    2-t-butyl-4-formyl-4-methyl-1,3-oxazolidine-3-carboxylic acid phenyl ester,
    3-benzoyl-2-t-butyl-4-methyl-1,3-oxazolidine-4-carbaldehyde,
    2-t-butyl-4-methyl-4-[2-(1-methyl-1H-pyrrol-2-yl)ethyl]-1,3-oxazolidine-3-carboxylic acid t-butyl ester,
    2-t-butyl-4-methyl-4-[2-(1-methyl-1H-pyrrol-2-yl)ethyl]-1,3-oxazolidine-3-carboxylic acid benzyl ester,
    2-t-butyl-4-methyl-4-[2-(1-methyl-1H-pyrrol-2-yl)ethyl]-1,3-oxazolidine-3-carboxylic acid methyl ester,
    2-t-butyl-4-methyl-4-[2-(1-methyl-1H-pyrrol-2-yl)ethyl]-1,3-oxazolidine-3-carboxylic acid phenyl ester,
    2-t-butyl-4-methyl-4-[2-(1-methyl-1H-pyrrol-2-yl)ethyl]-1,3-oxazolidine-3-carboxylic acid ethyl ester,
    3-acetyl-2-t-butyl-4-methyl-4-[2-(1-methyl-1H-pyrrol-2-yl)ethyl]-1,3-oxazolidine, and
    3-benzoyl-2-t-butyl-4-methyl-4-[2-(1-methyl-1H-pyrrol-2-yl)ethyl]-1,3-oxazolidine.
  14. A procedure for the preparation of a compound having the general formula (Ia) shown below by reacting a compound having the general formula (II) shown below with a compound having the general formula (III) in the presence of a base and a coordinating reagent in the presence or absence of a solvent,
    Figure imgb0065
     [wherein,
    R represents a C1-C6 alkyl group, a C2-C6 alkenyl group, a phenyl group or a benzyl group,
    R2 represents a C1-C6 alkyl group, a C3-C10 cycloalkyl group or a phenyl group,
    R3 represents a C2-C6 alkanoyl group, a C1-C6 alkyloxycarbonyl group, a benzoyl group, a phenyloxycarbonyl group or a benzyloxycarbonyl group]

            R4-Z     (III)

    [wherein,
    R4 represents a C1-C6 alkyl group or a C2-C6 alkenyl group,
    Z represents a halogen atom or a group having the general formula -O-S(O)2Rc, and
    Rc represents a methoxyl group, a C1-C6 alkyl group which may optionally be substituted with from 1 to 3 halogen atoms or a phenyl group which may optionally be substituted with from 1 to 3 substituents selected from the group consisting of a halogen atom and a methyl group]
    Figure imgb0066
     [wherein,
    R, R2, R3 and R4 have the same meanings as those indicated hereinbefore].
  15. A procedure for the preparation of a compound having the general formula (Ia) according to Claim 14, wherein the halogen atom represents a bromine atom or an iodine atom.
  16. A procedure for the preparation of a compound having the general formula (Ia) according to any one claim selected from Claim 14 and Claim 15, wherein the coordinating reagent employed is one reagent or at least two reagents selected from the group consisting of DMPU, DMI, NMP, DMAc, DMF, DMSO, diglyme, triglyme and tetraglyme.
  17. A procedure for the preparation of a compound having the general formula (Ia) according to any one claim selected from Claim 14 and Claim 15, wherein the coordinating reagent employed is triglyme or tetraglyme.
  18. A procedure for the preparation of a compound having the general formula (Ia) according to any one claim selected from Claim 14 to Claim 17, wherein the base employed is one base or at least two bases selected from the group consisting of LHMDS, LDA, SHMDS, KHMDS and potassium t-butoxide.
  19. A procedure for the preparation of a compound having the general formula (Ia) according to any one claim selected from Claim 14 to Claim 17, wherein the base employed is potassium t-butoxide.
  20. A procedure for the preparation of a compound having the general formula (Ia) according to any one claim selected from Claim 14 to Claim 19, wherein the solvent employed is one solvent or at least two solvents selected from the group consisting of tetrahydrofuran, 1,3-dioxolane, 1,4-dioxane and 1,2-dimethoxyethane.
  21. A procedure for the preparation of a compound having the general formula (Ia) according to any one claim selected from Claim 14 to Claim 19, wherein the solvent employed is tetrahydrofuran or 1,2-dimethoxyethane.
  22. A procedure for the preparation of a compound having the general formula (Ia) according to any one claim selected from Claim 14 to Claim 21, wherein the reaction temperature is between -25°C and 10°C.
  23. A procedure for the preparation of a compound having the general formula (Ia) according to any one claim selected from Claim 14 to Claim 22, wherein the base is added to the resulting mixture prepared by addition of the coordinating reagent, the compound having the general formula (II) and the compound having the general formula (III) to the solvent.
  24. A procedure for the preparation a compound having the general formula (Ib) shown below by reacting a compound having the general formula (Ia) shown below with a reducing reagent in a solvent,
    Figure imgb0067
     [wherein
    R represents a C1-C6 alkyl group, a C2-C6 alkenyl group, a phenyl group or a benzyl group,
    R2 represents a C1-C6 alkyl group, a C3-C10 cycloalkyl group or a phenyl group,
    R3 represents a C2-C6 alkanoyl group, a C1-C6 alkyloxycarbonyl group, a benzoyl group, a phenyloxycarbonyl group or a benzyloxycarbonyl group, and
    R4 represents a C1-C6 alkyl group or a C2-C6 alkenyl group]
    Figure imgb0068
     [wherein,
    R2, R3 and R4 have the same meanings as those indicated hereinbefore].
  25. A procedure for the preparation of a compound having the general formula (Ib) according to Claim 24, wherein the reducing agent employed is a combination of potassium borohydride and lithium chloride.
  26. A procedure for the preparation a compound having the general formula (Ic) shown below by reacting a compound having the general formula (Ib) shown below with an oxidizing agent in a solvent,
    Figure imgb0069
     [wherein,
    R2 represents a C1-C6 alkyl group, a C3-C10 cycloalkyl group or a phenyl group,
    R3 represents a C2-C6 alkanoyl group, a C1-C6 alkyloxycarbonyl group, a benzoyl group, a phenyloxycarbonyl group or a benzyloxycarbonyl group, and
    R4 represents a C1-C6 alkyl group or a C2-C6 alkenyl group]
    Figure imgb0070
     [wherein,
    R2, R3 and R4 have the same meanings as those indicated hereinbefore].
  27. A procedure for the preparation of a compound having the general formula (Ic) according to Claim 26, wherein the oxidizing agent employed is a combination of TEMPO, sodium bromide, sodium hypochloride and sodium hydrogencarbonate.
  28. A procedure for the preparation of a compound having the general formula (Ic) shown below by reacting a compound having the general formula (Ia) shown below with a reducing agent in a solvent,
    Figure imgb0071
     [wherein,
    R represents a C1-C6 alkyl group, a C2-C6 alkenyl group, a phenyl group or a benzyl group,
    R2 represents a C1-C6 alkyl group, a C3-C10 cycloalkyl group or a phenyl group,
    R3 represents a C2-C6 alkanoyl group, a C1-C6 alkyloxycarbonyl group, a benzoyl group, a phenyloxycarbonyl group or a benzyloxycarbonyl group, and
    R4 represents a C1-C6 alkyl group or a C2-C6 alkenyl group]
    Figure imgb0072
     [wherein,
    R2, R3 and R4 have the same meanings as those indicated hereinbefore].
  29. A procedure for the preparation of a compound having the general formula (Ic) according to Claim 28, wherein the reducing agent employed is sodium bis(2-methoxyethoxy)aluminum hydride.
  30. A procedure for the preparation of a compound having the general formula (Id) shown below by conducting a condensation reaction between a compound having the general formula (Ic) shown below and a compound having the general formula (IV) shown below in the presence of a base in a solvent, followed by hydrogenating the product thus obtained above,
    Figure imgb0073
     [wherein,
    R2 represents a C1-C6 alkyl group, a C3-C10 cycloalkyl group, or a phenyl group,
    R3 represents a C2-C6 alkanoyl group, a C1-C6 alkyloxycarbonyl group, a benzoyl group, a phenyloxycarbonyl group or a benzyloxycarbonyl group, and
    R4 represents a C1-C6 alkyl group or a C2-C6 alkenyl group]
    Figure imgb0074
     [wherein,
    W represents a phosphonium salt or a phosphonic acid ester,
    X represents a vinylene group, a sulfur atom, a nitrogen atom substituted with a C1-C6 alkyl group, a nitrogen atom substituted with a silyl group, a nitrogen atom substituted with an acyl group or an oxygen atom, and
    Y represents a hydrogen atom, a halogen atom, a cyano group, a C1-C8 alkyl group, a C1-C8 alkoxyl group or a C2-C8 alkanoyl group]
    Figure imgb0075
     [wherein,
    R2, R3, R4, X and Y have the same meanings as those indicated hereinbefore].
  31. A procedure for the preparation of a compound having the general formula (Id) according to Claim 30, wherein W is triphenylphosphonium iodide.
  32. A procedure for the preparation of a compound having the general formula (Id) according to Claim 30 or Claim 31, wherein the base employed is potassium t-butoxide.
  33. A procedure for the preparation of a compound having the general formula (IV') shown below which is characterized by reacting a compound having the general formula (IV") or a salt thereof with a compound having the general formula (A) in the presence of a compound having the general formula (B) in a solvent,
    Figure imgb0076
     [wherein,
    R5 represents a C1-C6 alkyl group which may optionally be substituted with substituent(s) selected from Substituent group α or a 5- to 10-membered aromatic group which may optionally be substituted with substituent(s) selected from Substituent group α, or two R5 groups together with the nitrogen atom to which they are bound form a 4-to 8-membered nitrogen-containing heterocyclic group which may optionally be substituted with substituent(s) selected from Substituent group α,
    X represents a vinylene group, a sulfur atom, a nitrogen atom substituted with a C1-C6 alkyl group, a nitrogen atom substituted with a silyl group, a nitrogen atom substituted with an acyl group or an oxygen atom,
    Y represents a hydrogen atom, a halogen atom, a cyano group, a C1-C8 alkyl group, a C1-C8 alkoxyl group or a C2-C8 alkanoyl group, and
    Substituent group α represents a halogen atom, a cyano group, a C1-C8 alkyl group, a C1-C8 alkoxyl group, a C1-C8 alkylthio group and an acyl group]
    Figure imgb0077
     [wherein,
    R6 represents a C1-C6 alkyl group which may optionally be substituted with substituent(s) selected from Substituent group α, a C1-C6 alkoxyl group which may optionally be substituted with substituent(s) selected from Substituent group α, a 5- to 10-membered aromatic group which may optionally be substituted with substituent(s) selected from Substituent group α, or a 5- to 10-membered aromatic-oxy group which may optionally be substituted with substituent(s) selected from Substituent group α, and Substituent group α has the same meaning as that described above]

            R7-V     (B)

    [wherein,
    R7 represents an acyl group,
    V represents a halogen atom or a group having the general formula -O-S(O)2Rc, and
    Rc represents a methoxyl group, a C1-C6 alkyl group which may optionally be substituted with from 1 to 3 halogen atoms or a phenyl group which may optionally be substituted with from 1 to 3 substituents selected from the group consisting of a halogen atom and a methyl group]
    Figure imgb0078
     [wherein,
    R6, V, X and Y have the same meanings as those described above].
  34. A procedure for the preparation of a compound having the general formula (IV') according to Claim 33, wherein X represents a nitrogen atom substituted with a methyl group.
  35. A procedure for the preparation of a compound having the general formula (IV') according to Claim 33 or Claim 34, wherein Y represents a hydrogen atom, a C1-C6 alkyl group or a C1-C6 alkoxyl group.
  36. A procedure for the preparation of a compound having the general formula (IV') according to any one claim selected from Claim 33 to Claim 35, wherein R5 represents a C1-C6 alkyl group or two R5 groups together with the nitrogen atom to which they are bound form a pyrrolidine or piperidine group.
  37. A procedure for the preparation of a compound having the general formula (IV') according to any one claim selected from Claim 33 to Claim 36, wherein R6 represents a phenyl group.
  38. A procedure for the preparation of a compound having the general formula (IV') according to any one claim selected from Claim 33 to Claim 37, wherein R7 represents a C1-C6 alkylcarbonyl group.
  39. A procedure for the preparation of a compound having the general formula (Id) by condensing a compound having the general formula (IV'), which is prepared by reacting a compound having the general formula (IV") or a salt thereof with a compound having the general formula (A) in the presence of a compound having the general formula (B) in a solvent, with a compound of the general formula (Ic) in the presence of a base in a solvent, followed by hydrogenation of the product thus obtained;
    Figure imgb0079
     [wherein,
    R5 represents a C1-C6 alkyl group which may optionally be substituted with substituent(s) selected from Substituent group α or a 5- to 10-membered aromatic group which may optionally be substituted with substituent(s) selected from Substituent group α, or two R5 groups together with the nitrogen atom to which they are bound form a 4-to 8-membered nitrogen-containing heterocyclic group which may optionally be substituted with substituent(s) selected from Substituent group α,
    X represents a vinylene group, a sulfur atom, a nitrogen atom substituted with a C1-C6 alkyl group, a nitrogen atom substituted with a silyl group, a nitrogen atom substituted with an acyl group or an oxygen atom,
    Y represents a hydrogen atom, a halogen atom, a cyano group, a C1-C8 alkyl group, a C1-C8 alkoxyl group or a C2-C8 alkanoyl group, and
    Substituent group α represents a halogen atom, a cyano group, a C1-C8 alkyl group, a C1-C8 alkoxyl group, a C1-C8 alkylthio group and an acyl group]
    Figure imgb0080
     [wherein,
    R6 represents a C1-C6-alkyl group which may optionally be substituted with substituent(s) selected from Substituent group α, a C1-C6 alkoxyl group which may optionally be substituted with substituent(s) selected from Substituent group α, a 5- to 10-membered aromatic group which may optionally be substituted with substituent(s) selected from Substituent group α, or a 5- to 10-membered aromatic-oxy group which may optionally be substituted with substituent(s) selected from Substituent group α, and Substituent group α has the same meaning as that described above]

            R7-V     (B)

    [wherein,
    R7 represents an acyl group,
    V represents a halogen atom or a group having the general formula -O-S(O)2Rc, and
    Rc represents a methoxyl group, a C1-C6 alkyl group which may optionally be substituted with from 1 to 3 halogen atoms or a phenyl group which may optionally be substituted with from 1 to 3 substituents selected from the group consisting of a halogen atom and a methyl group]
    Figure imgb0081
     [wherein,
    R6, V, X and Y have the same meanings as those described above]
    Figure imgb0082
     [wherein,
    R2 represents a C1-C6 alkyl group, a C3-C10 cycloalkyl group or a phenyl group,
    R3 represents a C2-C6 alkanoyl group, a C1-C6 alkyloxycarbonyl group, a benzoyl group, a phenyloxycarbonyl group or a benzyloxycarbonyl group, and
    R4 represents a C1-C6 alkyl group or a C2-C6 alkenyl group]
    Figure imgb0083
     [wherein,
    R2, R3, R4, X and Y have the same meanings as those indicated hereinbefore].
EP05799393A 2004-10-28 2005-10-26 Optically active 4,4-disubstituted oxazolidine derivative and method for producing same Withdrawn EP1806344A4 (en)

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US8722714B2 (en) * 2008-01-16 2014-05-13 The Honk Kong University of Science and Technology Oxazolidine derivatives as NMDA antagonists

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